Treatment of Aging-Associated Disease with Modulators of Leukotriene A4 Hydrolase

ABSTRACT

Methods and compositions for treating and/or preventing aging-related conditions are described. The compositions used in the methods include inhibitors or antagonists of leukotriene A4 hydrolase (“LTA4H”) with efficacy in treating and/or preventing aging-related conditions such as neurocognitive disorders.

I. CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. § 119 (e), this application claims priority to thefiling dates of: United States Provisional Patent Application No.62/671,882, filed May 15, 2018 and U.S. Provisional Patent ApplicationNo. 62/694,921, filed Jul. 6, 2018; the disclosures of whichapplications are herein incorporated by reference.

II. INTRODUCTION Field

This invention pertains to the prevention and treatment ofaging-associated disease. The invention relates to the use of modulatorsof leukotriene A4 hydrolase (“LTA4H”), to treat and/or preventconditions associated with aging, such as cognitive disorders, motordisorders, and neuroinflammation.

Background

The following is offered as background information only and is notadmitted as prior art to the present invention.

Aging is an important risk factor for multiple human diseases includingcognitive impairment, cancer, arthritis, vision loss, osteoporosis,diabetes, cardiovascular disease, and stroke. In addition to normalsynapse loss during natural aging, synapse loss is an early pathologicalevent common to many neurodegenerative conditions and is the bestcorrelate to the neuronal and cognitive impairment associated with theseconditions. As such, aging remains the single most dominant risk factorfor dementia-related neurodegenerative diseases such as Alzheimer'sdisease (AD) (Bishop N. A. et al., Neural mechanisms of ageing andcognitive decline. Nature 464(7288), 529-535 (2010); Heeden T. et al.,Insights into the ageing mind: a view from cognitive neuroscience. Nat.Rev. Neurosci. 5(2), 87-96 (2004); Mattson, M. P., et al., Ageing andneuronal vulnerability. Nat. Rev. Neurosci. 7(4), 278-294 (2006)).Similarly, a decline in motor skills correlates with aging. (Hoogendam YY, et al., Older Age Relates to Worsening of Fine Motor Skills: APopulation-Based Study of Middle-Aged and Elderly Persons. Front. AgingNeurosci. 6 (2014)). Additionally, neuroinflammation has been associatedwith aging in both healthy brains and in diseased brains such as in AD.(Lynch M A, Age-related neuroinflammatory changes negatively impact onneuronal function. Front. Aging Neurosci. 1(6), 1-8 (2010)). Agingaffects all tissues and functions of the body including the centralnervous system, and neurodegeneration and a decline in functions such ascognition or motor skills, can severely impact quality of life.Treatment for cognitive decline, motor impairment, neuroinflammation,and neurodegenerative disorders has had limited success in preventingand reversing impairment. It is therefore important to identify newtreatments for maintaining cognitive and motor integrity by protectingagainst, countering, or reversing the effects of aging.

Leukotriene A4 hydrolase (“LTA₄H” or “LTA4H”) is a soluble, monomericenzyme that converts lipid metabolite leukotriene A4 (“LTA₄” or “LTA4”)to leukotriene B4 (“LTB₄” or “LTB4”). The LTA₄H enzyme through itsability to produce the LTB4 lipid metabolite has been characterized asproinflammatory. Additionally, LTB4 lipid metabolite is associated withneutrophil recruitment. Thus, the LTA4H enzyme has been implicated insuch diseases as atherosclerosis, atherosclerotic coronary arterydisease, rheumatoid arthritis, cystic fibrosis, chronic obstructivepulmonary disease, sepsis, adult respiratory distress syndrome,inflammatory bowel disease, and asthma. (Snelgrove R J, Leukotriene A4Hydrolase: An Anti-Inflammatory Role for A Proinflammatory Enzyme,Thorax 66:550-51 (2011); Shim Y M, et al., Leukotriene A4 Hydrolase AnEvolving Therapeutic Target, Inflammatory Diseases—Immunopathology,Clinical and Pharmacological Bases (Dr. Mahin Khatami (Ed.)), 253-278,(2012)).

The LTA4H enzyme has recently been characterized as having an additionalcatalytic activity. LTA4H not only exhibits the epoxide hydrolaseactivity converting LTA4 to LTB4, but an additional aminopeptidaseactivity (or “peptidase” activity), cleaving Pro-Gly-Pro peptides(P-G-P) to Pro+Gly−Pro. This aminopeptidase activity is thought tocontribute an anti-inflammatory role for LTA4H by reducing accumulationof P-G-P. (Snelgrove, et al. A critical role for LTA4H in limitingchronic pulmonary neutrophilic inflammation, Science 330(6000):90-4(2010)). This discovery may provide insights into the clinical failuresof LTA4H inhibitors within inflammatory diseases. Modulators of theLTA4H enzyme have been described, including small molecule inhibitors.These include small molecules that: bind both the epoxide hydrolasepocket and the aminopeptidase active site, such as SC-57461A; andselectively bind the epoxide hydrolase binding pocket of LTA4H, such aspinostilbene hydrate (Low C M et al., The development of novel LTA4Hmodulators to selectively target LTB4 generation. Sci. Rep. 7, 44449(2017)).

The second class of Leukotrienes (“LTs”) are the cysteinyl leukotrienes(Cys-LT), LTC4, LTD4, and LTE4, which are ligands for the cysteinylleukotriene receptors type 1 and 2 (CysLT1R, CysLT2R), GPR17, andothers. (Ghosh, A., et al., Cysteinyl Leukotrienes and Their Receptors:Emerging Therapeutic Targets in Central Nervous System Disorders. CNSNeurosci Ther, 22(12): p. 943-51 (2016)). LTs in general have beenassociated with inflammation and studied for their role in diseases suchas asthma. (Y. Michael Shim, M. P., Leukotriene A4 Hydrolase—An EvolvingTherapeutic Target in Inflammatory Diseases—Immunopathology, Clinicaland Pharmacological Bases, M. Khatami, Editor. InTech. p. 253-78(2012)). More recently, Cys-LTs have been shown to influence centralnervous system diseases including traumatic brain injury, Alzheimer'sdisease (AD), Parkinson's disease, multiple sclerosis, epilepsy,Huntington's disease, and depression. (Ghosh A, supra). For example,LTD4 and CysLT1R are increased in transgenic mouse models of AD andadministration of CysLT1R antagonists, Pranlukast and Montelukast,alleviate some of the pathological symptoms in these mice. (Tang, S. S.,et al., Protective effect of pranlukast on Abeta(1)(-)(4)(2)-inducedcognitive deficits associated with downregulation of cysteinylleukotriene receptor 1. Int J Neuropsychopharmacol, 17(4): p. 581-92(2014); Tang, S. S., et al., Leukotriene D4 induces cognitive impairmentthrough enhancement of CysLT(1) R-mediated amyloid-beta generation inmice. Neuropharmacology, 65: p. 182-92 (2013); Wang, X. Y., et al.,Leukotriene D4 induces amyloid-beta generation via CysLT(1)R-mediatedNF-kappaB pathways in primary neurons. Neurochem Int, 62(3): p. 340-47(2013); and Herbst-Robinson, K. J., et al., Inflammatory EicosanoidsIncrease Amyloid Precursor Protein Expression via Activation of MultipleNeuronal Receptors. Sci Rep, 5: p. 18286 (2015)), Additionally,administration of Montelukast in aged mice reduces brain inflammation,increases neurogenesis, and improves cognition. (Marschallinger, J., etal., Structural and functional rejuvenation of the aged brain by anapproved anti-asthmatic drug. Nat Commun, 6: p. 8466 (2015)). While theCys-LTs have been shown to influence the CNS, the production of LTB4 byLTA4H has not be implicated in cognition or diseases of the CNS.

III. SUMMARY

The present invention recognizes that as people age, the amounts ofcertain plasma proteins also increase. The present invention recognizesthat such proteins can be referred to as “pro-aging factors,” andmodulation of their activity or concentration in the blood circulationcan protect or even reverse certain aging-related symptoms and/ordisease. The present invention is also based on work demonstrating thatthe LTA4H enzyme and its product LTB4 occur at higher concentrations inolder subjects than in younger subjects. The present invention showsthat the introduction of exogenous LTA4H enzyme in vivo results in areduction of cognitive ability, neuronal cell survival, andproliferation of neural stem/progenitor cells in young animals. Thepresent also demonstrates, among other things, that modulation of theLTA4H enzyme through pharmacological intervention in vivo leads to animprovement in cognition and reduction in inflammatory markers in agedanimals. The present invention also recognizes that modulation of theLTA4H enzyme through pharmacological intervention may cause a reductionin the progression or reverse certain aging-associated symptoms ordisease.

The present invention is based on targeting the LTA4H enzyme fortreating and/or preventing age-related disorders, such as cognitiveimpairment conditions, age-related dementia, impairment of motorfunction, neuroinflammation, and neurodegenerative disease. The presentinvention recognizes, among other things, the need for new therapies andnew mechanisms of action for the treatment and/or prevention ofcognitive impairment, age-related dementia, motor impairment,neuroinflammation, and neurodegenerative disease. The presentcompositions of the invention relate to a solution for the failures andshortcomings of current therapies through utilization of inhibitors ofthe LTA4H enzyme in the treatment and/or prevention of cognitiveimpairment, age-related dementia, motor impairment, neuroinflammation,and neurodegenerative disease.

An embodiment of the invention includes treating a subject diagnosedwith a cognitive impairment by administering to the subject an effectiveamount of one or more LTA4H modulatory agents. Another embodiment of theinvention includes administering the effective amount of one or moreLTA4H modulatory agents and subsequently monitoring the subject forimproved cognitive function. Another embodiment of the inventionincludes treating a subject diagnosed with a cognitive impairment byadministering to the subject an effective amount of one or more LTA4Hmodulatory agents wherein the one or more LTA4H modulatory agents areadministered in a manner resulting in improved cognitive function,improved neurogenesis, or reduced neuroinflammation.

An embodiment of the invention includes treating a subject diagnosedwith a neurodegenerative motor disorder such as, by way of example andnot limitation, Parkinson's Disease, by administering to the subject aneffective amount of one or more LTA4H modulatory agents. Anotherembodiment of the invention includes administering the effective amountof one or more LTA4H modulatory agents and subsequently monitoring thesubject for improved motor function. Another embodiment of the inventionincludes treating a subject diagnosed with a neurodegenerative motordisorder by administering to the subject an effective amount of one ormore LTA4H modulatory agents wherein the one or more LTA4H modulatoryagents are administered in a manner resulting in improved motorfunction, neurogenesis, or reduced neuroinflammation.

An embodiment of the invention includes treating a subject diagnosedwith neuroinflammation or a neuroinflammation-associated disorder byadministering to the subject an effective amount of one or more LTA4Hmodulatory agents. Another embodiment of the invention includesadministering the effective amount of one or more LTA4H modulatoryagents and subsequently monitoring the subject for reducedneuroinflammation. Another embodiment of the invention includes treatinga subject diagnosed with neuroinflammation or aneuroinflammation-associated disorder by administering to the subject aneffective amount of one or more LTA4H modulatory agents wherein the oneor more LTA4H modulatory agents are administered in a manner resultingin reduced neuroinflammation.

Another embodiment of the invention includes utilizing an inhibitor ofthe LTA4H enzyme as the one or more LTA4H modulatory agent(s). Furtherembodiments contemplate using one or more LTA4H modulatory agent(s) thatselectively inhibits the epoxide hydrolase activity of LTA4H, and notthe aminopeptidase activity of LTA4H. A further embodiment contemplatesusing one or more LTA4H modulatory agent(s) that inhibits both theepoxide hydrolase activity of LTA4H and the aminopeptidase activity ofLTA4H. A further embodiment of the invention contemplates the LTA4Hmodulatory agent(s) having the ability to selectively bind to one ormore sites on the LTA4H enzyme, such as by way of example and notlimitation, the epoxide hydrolase active site and/or the aminopeptidaseactive site.

An embodiment of the invention includes treating a subject diagnosedwith a cognitive impairment, impaired motor function, orneuroinflammation or a decline in neurogenesis by administering to thesubject an effective amount of one or more LTA4H modulatory agent(s),with the subject following an exercise regimen after the administration.Another embodiment of the invention includes following an exerciseregimen that is prescribed to the subject. Another embodiment of theinvention includes the subject exercising at a higher intensity and/orgreater frequency than the subject exercised preceding theadministration. Another embodiment of the invention includes the subjectexercising at a similar intensity and/or frequency as the subjectexercised preceding the administration.

IV. INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

V. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts the concentration of LTA4H in young (18-year-old) andold (65-year-old) human plasma.

FIG. 1B depicts the concentration of LTB4 in young (18-year-old) and old(65-year-old) human plasma.

FIG. 2A depicts the concentration of LTB4 in young (3 month, 3M) and old(22.5 month, 22.5M) mouse plasma.

FIG. 2B depicts the concentration of LTB4 in young (3 month, 3M) and old(22.5 month, 22.5M) mouse plasma either unstimulated or stimulated withcalcimycin to increase LTB4 production.

FIG. 3 depicts treatment paradigm 1 of LTA4H recombinant protein orphosphate buffered saline (PBS) administration in 8-week old (young)wild-type (C57BL/6) mice.

FIG. 4A reports the total distance travelled in an open field test inyoung mice treated with recombinant human LTA4H protein or phosphatebuffered saline (PBS) control.

FIG. 4B reports the average velocity in an open field test in young micetreated with recombinant human LTA4H protein or phosphate bufferedsaline (PBS) control.

FIG. 4C reports the percent time spent in the periphery or center in anopen field test in young mice treated with recombinant human LTA4Hprotein or phosphate buffered saline (PBS) control.

FIG. 5A depicts the percent time spent freezing in 30 sec bins in acontextual fear conditioning task in young mice treated with recombinanthuman LTA4H protein or phosphate buffered saline (PBS) control.

FIG. 5B depicts the percent time spent freezing during the wholeduration of the contextual fear conditioning task in young mice treatedwith recombinant human LTA4H protein or phosphate buffered saline (PBS)control.

FIG. 5C depicts the time spent freezing pre and post-cue tone in a cuedfear conditioning task in young mice treated with recombinant humanLTA4H protein or phosphate buffered saline (PBS) control.

FIG. 6 reports the number of EdU-labeled cells within granule cell layerof the hippocampus in young mice treated with recombinant human LTA4Hprotein or phosphate buffered saline (PBS) control.

FIG. 7 depicts cell nuclei labeled with DAPI (blue) and dividing Ki67(green) labeled cells in the dentate gyrus in young mice treated withrecombinant human LTA4H protein or phosphate buffered saline (PBS)control.

FIG. 8 reports the number of Ki67-labeled dividing cells in the blade ofthe dentate gyrus in the hippocampus in young mice treated withrecombinant human LTA4H protein or phosphate buffered saline (PBS)control.

FIG. 9 reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of vesicular glutamate receptor (vglut1),synapsin 1 (syn1), synaptophysin (syp), early growth response 1 (egr1),doublecortin (dcx), beta III tubulin (tuj1), glial acidic fibrillaryprotein (gfap), SRY-Box 2 (sox2), and oligodendrocyte transcriptionfactor 2 in young mice treated with recombinant human LTA4H protein orphosphate buffered saline (PBS) control.

FIG. 10 depicts treatment paradigm 2 of LTA4H recombinant proteinadministered for 1 week at the start of the study (pulse) orcontinuously for 6 weeks, or phosphate buffered saline (PBS) in 8-weekold (young) wild-type (C57BL/6) mice.

FIG. 11A reports the total distance travelled in an open field test inyoung mice treated with recombinant human LTA4H protein or phosphatebuffered saline (PBS) control.

FIG. 11B reports the average velocity in an open field test in youngmice treated with recombinant human LTA4H protein or phosphate bufferedsaline (PBS) control.

FIG. 11C reports the percent time spent in the periphery or center in anopen field test in young mice treated with recombinant human LTA4Hprotein or phosphate buffered saline (PBS) control.

FIG. 12A reports the number entries made into the familiar arm duringtraining of the Y-maze task of young mice treated with recombinant humanLTA4H protein or phosphate buffered saline (PBS).

FIG. 12B reports the percentage of the number of entries into the noveland familiar arms of the Y-maze during testing in young mice treatedwith recombinant human LTA4H protein or phosphate buffered saline (PBS).

FIG. 13 reports the number of BrdU and DCX co-labeled cells withingranule cell layer of the hippocampus in young mice treated withrecombinant human LTA4H protein or phosphate buffered saline (PBS)control.

FIG. 14 reports the average number of Iba1-labled microglia in thehippocampus in young mice treated with recombinant human LTA4H proteinor phosphate buffered saline (PBS) control.

FIG. 15 depicts treatment paradigm 3 of LTA4H recombinant protein orphosphate buffered saline (PBS) administration in 8-week old (young)wild-type (C57BL/6) mice.

FIG. 16 reports the average number of CD68 puncta in the hippocampus inyoung mice treated with recombinant human LTA4H protein or phosphatebuffered saline (PBS) control.

FIG. 17A displays a schematic of the LTA4H biochemical signalingpathway.

FIG. 17B displays a key to accompany the schematic in FIG. 17A.

FIG. 18A reports the total distance travelled in an open field test inaged mice treated for one month with vehicle, the LTA4H hydrolase andpeptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696,the cysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 18B reports the average velocity in an open field test in aged micetreated for one month with vehicle, the LTA4H hydrolase and peptidaseinhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696, thecysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 18C reports the percent time spent in the periphery or center in anopen field test in aged mice treated for one month with vehicle, theLTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4 receptorinhibitor CP 105,696, the cysteinyl leukotriene receptor inhibitorMontelukast, and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 19A reports the latency to find the platform in the radial armwater maze in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 19B reports the number of errors made in finding the platform inthe radial arm water maze in aged mice treated for one month withvehicle, the LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4receptor inhibitor CP 105,696, the cysteinyl leukotriene receptorinhibitor Montelukast, and the LTA4H hydrolase inhibitor pinostilbenehydrate.

FIG. 19C reports the latency to find the platform in the last two trialsof training of the radial arm water maze in aged mice treated for onemonth with vehicle, the LTA4H hydrolase and peptidase inhibitor SC57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinylleukotriene receptor inhibitor Montelukast, and the LTA4H hydrolaseinhibitor pinostilbene hydrate.

FIG. 19D reports the latency to find the platform in the last two trialsof testing of the radial arm water maze in aged mice treated for onemonth with vehicle, the LTA4H hydrolase and peptidase inhibitor SC57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinylleukotriene receptor inhibitor Montelukast, and the LTA4H hydrolaseinhibitor pinostilbene hydrate.

FIG. 19E reports the number of errors made in finding the platform inthe last two trials of training of the radial arm water maze in agedmice treated for one month with vehicle, the LTA4H hydrolase andpeptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696,the cysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 19F reports the number of errors made in finding the platform inthe last two trials of testing of the radial arm water maze in aged micetreated for one month with vehicle, the LTA4H hydrolase and peptidaseinhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696, thecysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 20A reports the percentage of the number of entries into the noveland familiar arms of the Y-maze during testing in aged mice treated forone month with vehicle, the LTA4H hydrolase and peptidase inhibitor SC57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinylleukotriene receptor inhibitor Montelukast, and the LTA4H hydrolaseinhibitor pinostilbene hydrate.

FIG. 20B reports the total distance traveled in the Y-maze duringtesting in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 21A reports the average integrated optical density of aquaporin-4(AQP4) in the hippocampus of aged mice treated for one month withvehicle, the LTA4H hydrolase and peptidase inhibitor SC 57461A, the LTB4receptor inhibitor CP 105,696, the cysteinyl leukotriene receptorinhibitor Montelukast, and the LTA4H hydrolase inhibitor pinostilbenehydrate.

FIG. 21B reports the average fluorescence intensity of aquaporin-4(AQP4) in the perivascular space in the hippocampus of aged mice treatedfor one month with vehicle, the LTA4H hydrolase and peptidase inhibitorSC 57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinylleukotriene receptor inhibitor Montelukast, and the LTA4H hydrolaseinhibitor pinostilbene hydrate.

FIG. 21C reports the average fluorescence intensity of aquaporin-4(AQP4) immediately surround blood vessels (vascular) of hippocampus ofaged mice treated for one month with vehicle, the LTA4H hydrolase andpeptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696,the cysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 22 reports the total plasma concentrations of LTB4 measured byELISA in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 23A-F reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of ionized calcium-binding adaptermolecule 1 (Iba-1), interleukin 6 (IL-6), interleukin 1-beta (IL-1β),Eotaxin, nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB), and tumor necrosis factor alpha (TNFα) in aged mice treated forone month with vehicle, the LTA4H hydrolase and peptidase inhibitor SC57461A, the LTB4 receptor inhibitor CP 105,696, the cysteinylleukotriene receptor inhibitor Montelukast, and the LTA4H hydrolaseinhibitor pinostilbene hydrate.

FIG. 24A reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of the neuronal genes tuj1, syn1, dlg4,and bdnf in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 24B reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of microglia genes, cluster ofdifferentiation molecule 11 b (CD11b), interleukin 18 (IL-18), clusterof differentiation (CD68), interleukin 1α (IL-1α), interleukin 4 (IL-4),insulin-like growth factor 1 (IGF-1), and transforming growth factor β(TGFβ) in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

FIG. 24C reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels astrocytic genes, aquaporin 4 (aqp4),glial acidic fibrillary protein (gfap), six transmembrane epithelialantigen of prostate 4 (steap4), sphingosine-1-phosphate receptor 1(slpr3), tissue inhibitor of metalloproteinases (timp1), H2 class Ihistocompatibility antigen (h2d1), guanylate-binding protein 2 (gbp2),N-acetyllactosaminide alpha-1 3-galactosyltransferase (ggta1), H2T23protein (h2t23), and cardiotrophin-like cytokine factor 1 (cicf1) inaged mice treated for one month with vehicle, the LTA4H hydrolase andpeptidase inhibitor SC 57461A, the LTB4 receptor inhibitor CP 105,696,the cysteinyl leukotriene receptor inhibitor Montelukast, and the LTA4Hhydrolase inhibitor pinostilbene hydrate.

FIG. 24D reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of immediate early genes, cfos, egr1, andcreb1 in aged mice treated for one month with vehicle, the LTA4Hhydrolase and peptidase inhibitor SC 57461A, the LTB4 receptor inhibitorCP 105,696, the cysteinyl leukotriene receptor inhibitor Montelukast,and the LTA4H hydrolase inhibitor pinostilbene hydrate.

VI. DETAILED DESCRIPTION A. Introduction

The present invention relates to the identification and discovery ofmethods and compositions for the treatment and/or prevention ofcognitive and motor impairment, including age-associated dementia,decline in motor skills, neuroinflammation, and neurodegenerativedisease. Described herein are methods and compositions for the treatmentof subjects suffering from such disorders, which are aspects of thepresent invention. The methods and compositions described herein areuseful in: preventing or treating cognitive or motor impairment,age-associated dementia or motor impairment, neuroinflammation, andneurodegenerative disease; ameliorating the symptoms of cognitive ormotor impairment, age-associated dementia or motor impairment,neuroinflammation, and neurodegenerative disease; slowing progression ofaging-associated cognitive or motor impairment, age-associated dementiaor motor impairment, neuroinflammation, and neurodegenerative disease;and/or reversing the progression of aging-associated cognitive or motorimpairment, age-associated dementia or motor impairment,neuroinflammation, and neurodegenerative disease. An implementation ofthe invention includes using the LTA4H modulatory agent(s) as treatment.An embodiment of the invention includes the LTA4H modulatory agent(s).Another embodiment of the invention includes using an LTA4H modulatingagent which selectively inhibits the epoxide hydrolase activity of theLTA4H enzyme. Another embodiment of the invention includes using anLTA4H modulating agent which inhibits both the epoxide hydrolaseactivity and the aminopeptidase activity of the LTA4H enzyme. Anotherembodiment of the invention includes one or more LTA4H modulatingagent(s) that bind to the epoxide hydrolase and/or aminopeptidase activesite(s).

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to a particular method orcomposition described, as such may, of course, vary. It is alsounderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

It is noted that the claims may be drafted to exclude any optionalelement. As such, this statement is intended to serve as antecedentbasis for use of such exclusive terminology as “solely,” “only” and thelike in connection with the recitation of claim elements or use of a“negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein have discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or the spirit of thepresent invention. Any recited method can be carried out in the order ofevents recited or in any other order which is logically possible.

While the apparatus and method has or will be described for the sake ofgrammatical fluidity with functional explanations, it is to be expresslyunderstood that the claims, unless expressly formulated under 35 U.S.C.§ 112, are not to be construed as necessarily limited in any way by theconstruction of “means” or “steps” limitations, but are to be accordedthe full scope of the meaning and equivalents of the definition providedby the claims under the judicial doctrine of equivalents, and in thecase where the claims are expressly formulated under 35 U.S.C. § 112 areto be accorded full statutory equivalents under 35 U.S.C. § 112.

B. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the present invention, some potentialand preferred methods and materials are now described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It is understood that the present disclosuresupersedes any disclosure of an incorporated publication to the extentthere is a contradiction.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acell” includes a plurality of such cells and reference to “the peptide”includes reference to one or more peptides and equivalents thereof, e.g.polypeptides, known to those having skill in the art, and so forth.

In describing methods of the present invention, the terms “host”,“subject”, “individual” and “patient” are used interchangeably and referto any mammal in need of such treatment according to the disclosedmethods. Such mammals include, e.g., humans, ovines, bovines, equines,porcines, canines, felines, non-human primate, mice, and rats. Incertain embodiments, the subject is a non-human mammal. In someembodiments, the subject is a farm animal. In other embodiments, thesubject is a pet. In some embodiments, the subject is mammalian. Incertain instances, the subject is human. Other subjects can includedomestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats,horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g.,as in animal models of disease), as well as non-human primates (e.g.,chimpanzees, and monkeys). As such, subjects of the invention, includebut are not limited to mammals, e.g., humans and other primates, such aschimpanzees and other apes and monkey species; and the like, where incertain embodiments the subject are humans. The term subject is alsomeant to include a person or organism of any age, weight or otherphysical characteristic, where the subjects may be an adult, a child, aninfant or a newborn.

By a “young” or “young individual” it is meant an individual that is ofchronological age of 40 years old or younger, e.g., 35 years old oryounger, including 30 years old or younger, e.g., 25 years old oryounger or 22 years old or younger. As such, “young” and “youngindividual” may refer to a subject that is between the ages of 0 and 40,e.g., 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40 years old. In otherinstances, “young” and “young individual” may refer to a biological (asopposed to chronological) age such as an individual who has notexhibited the levels of inflammatory cytokines in the plasma exhibitedin comparatively older individuals. Conversely, these “young” and “youngindividual” may refer to a biological (as opposed to chronological) agesuch as an individual who exhibits greater levels of anti-inflammatorycytokines in the plasma compared to levels in comparatively olderindividuals. By way of example, and not limitation, the inflammatorycytokine is Eotaxin, and the fold difference between a young subject oryoung individual and older individuals is at least 1.5-fold. Similarly,the fold difference between older and younger individuals in otherinflammatory cytokines may be used to refer to a biological age. (SeeU.S. patent application Ser. No. 13/575,437 which is herein incorporatedby reference). Usually, the individual is healthy, e.g., the individualhas no hematological malignancy or autoimmune disease at the time ofharvest.

By “an individual suffering from or at risk of suffering from anaging-associated impairment” is meant an individual that is about morethan 50% through its expected lifespan, such as more than 60%, e.g.,more than 70%, such as more than 75%, 80%, 85%, 90%, 95% or even 99%through its expected lifespan. The age of the individual will depend onthe species in question. Thus, this percentage is based on the predictedlife-expectancy of the species in question. For example, in humans, suchan individual is 50 year old or older, e.g., 60 years old or older, 70years old or older, 80 years old or older, 90 years old or older, andusually no older than 100 years old, such as 90 years old, i.e., betweenthe ages of about 50 and 100, e.g., 50 . . . 55 . . . 60 . . . 65 . . .70 . . . 75 . . . 80 . . . 85 . . . 90 . . . 95 . . . 100 years old orolder, or any age between 50-1000, that suffers from an aging-associatedcondition as further described below, e.g., cognitive or motorimpairment associated with the natural aging process; an individual thatis about 50 years old or older, e.g., 60 years old or older, 70 yearsold or older, 80 years old or older, 90 years old or older, and usuallyno older than 100 years old, i.e., between the ages of about 50 and 100,e.g., 50 . . . 55 . . . 60 . . . 65 . . . 70 . . . 75 . . . 80 . . . 85. . . 90 . . . 95 . . . 100 years old, that has not yet begun to showsymptoms of an aging-associated condition e.g., cognitive or motorimpairment; an individual of any age that is suffering from a cognitiveor motor impairment due to an aging-associated disease, as describedfurther below, and an individual of any age that has been diagnosed withan aging-associated disease that is typically accompanied by cognitiveor motor impairment, where the individual has not yet begun to showsymptoms of cognitive or motor impairment. The corresponding ages fornon-human subjects are known and are intended to apply herein.

As used herein, “treatment” refers to any of (i) the prevention of thedisease or disorder, or (ii) the reduction or elimination of symptoms ofthe disease or disorder. Treatment may be effected prophylactically(prior to the onset of disease) or therapeutically (following the onsetof the disease). The effect may be prophylactic in terms of completelyor partially preventing a disease or symptom thereof and/or may betherapeutic in terms of a partial or complete cure for a disease and/oradverse effect attributable to the disease. Thus, the term “treatment”as used herein covers any treatment of an aging-related disease ordisorder in a mammal and includes: (a) preventing the disease fromoccurring in a subject which may be predisposed to the disease but hasnot yet been diagnosed as having it; (b) inhibiting the disease, i.e.,arresting its development; or (c) relieving the disease, i.e., causingregression of the disease. Treatment may result in a variety ofdifferent physical manifestations, e.g., modulation in gene expression,rejuvenation of tissue or organs, etc. The therapeutic agent may beadministered before, during or after the onset of disease. The treatmentof ongoing disease, where the treatment stabilizes or reduces theundesirable clinical symptoms of the patient, is of particular interest.Such treatment may be performed prior to complete loss of function inthe affected tissues. The subject therapy may be administered during thesymptomatic stage of the disease, and in some cases after thesymptomatic stage of the disease. In another embodiment of theinvention, “treatment” refers to reducing local tissue or blood levelsof neutrophils to a more homeostatic state, i.e. to levels observed in ahealthy individual of the same or similar age.

In some embodiments, the aging-associated condition that is treated isan aging-associated impairment in cognitive ability in an individual. Bycognitive ability, or “cognition,” it is meant the mental processes thatinclude attention and concentration, learning complex tasks andconcepts, memory (acquiring, retaining, and retrieving new informationin the short and/or long term), information processing (dealing withinformation gathered by the five senses), visuospatial function (visualperception, depth perception, using mental imagery, copying drawings,constructing objects or shapes), producing and understanding language,verbal fluency (word-finding), solving problems, making decisions, andexecutive functions (planning and prioritizing). By “cognitive decline”,it is meant a progressive decrease in one or more of these abilities,e.g., a decline in memory, language, thinking, judgment, etc. By “animpairment in cognitive ability” and “cognitive impairment”, it is meanta reduction in cognitive ability relative to a healthy individual, e.g.,an age-matched healthy individual, or relative to the ability of theindividual at an earlier point in time, e.g., 2 weeks, 1 month, 2months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years ormore previously. By “aging-associated cognitive impairment,” it is meantan impairment in cognitive ability that is typically associated withaging, including, for example, cognitive impairment associated with thenatural aging process, e.g., mild cognitive impairment (M.C.I.); andcognitive impairment associated with an aging-associated disorder, thatis, a disorder that is seen with increasing frequency with increasingsenescence, e.g., a neurodegenerative condition such as Alzheimer'sdisease, Parkinson's disease, frontotemporal dementia, Huntingtondisease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma,myotonic dystrophy, vascular dementia, and the like.

In some embodiments, the aging-associated condition that is treated isan aging-associated impairment in motor ability in an individual. Bymotor ability, it is meant the motor processes that include the abilityto perform complex muscle-and-nerve actions that produce movement suchas fine motor skills producing small or precise movements (e.g. writing,tying shoes) and gross motor skills for large movements (e g walking,running, kicking). By “motor decline”, it is meant a progressivedecrease in one or more of these abilities, e.g., a decline in findmovement or gross motor skills, etc. By “motor impaired” and “motorimpairment”, it is meant a reduction in motor ability/skills relative toa healthy individual, e.g., an age-matched healthy individual, orrelative to the ability of the individual at an earlier point in time,e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5years, or 10 years or more previously. By “aging-associated motorimpairment,” it is meant an impairment or decline in motor ability thatis typically associated with aging, including, for example, motorimpairment associated with the natural aging process and motorimpairment or decline associated with an aging-associated disorder, thatis, a disorder that is seen with increasing frequency with increasingsenescence, e.g., a neurodegenerative condition such as Parkinson'sdisease, amyotrophic lateral sclerosis, and the like.

In some embodiments, the aging-associated condition that is treated isan aging-associated increase in neuroinflammation in an individual. By“neuroinflammation” it is meant biochemical and cellular responses ofthe nervous system to injury, infection, or neurodegenerative diseases.Such responses are directed at decreasing the triggering factors byinvolving central nervous system immunity to defend against potentialharm. Neurodegeneration occurs in the central nervous system andexhibits hallmarks of loss of neuronal structure and function.Neuroinflammatory diseases or neuroinflammatory-associated conditions ordiseases, includes by way of example and not limitation,neurodegenerative diseases such as Alzheimer's disease; Parkinson'sdisease, multiple sclerosis and the like.

C. Treatment

Aspects of the methods of the inventions described herein includetreatment of a subject with an LTA4H modulatory agent, e.g., asdescribed above. An embodiment includes treatment of a human subjectwith an LTA4H modulatory agent. One of skill in the art would recognizethat methods of treatment of subjects with LTA4H modulatory agents arerecognized in the art. By way of example, and not limitation, oneembodiment of the methods of the inventions described herein iscomprised of administering an LTA4H modulatory agent to a subject fortreatment and/or prevention of cognitive impairment and/or age-relateddementia. The LTA4H modulatory agent may be administered through one ormore routes such as IP, IV, PO, and the like. Additionally, the LTA4Hmodulatory agent may be administered one or more time per day, such asonce per day, twice per day, thrice per day, four time per day, etc.,and such doses may be administered chronically (e.g. greater that onemonth, greater than two months, greater than 3 to five months, greaterthan six months, greater than one year, etc.), or acutely for a shortertime span (e.g. shorter than one month).

Aspects of the methods described herein include use of LTA4H modulatoryagents. Any convenient LTA4H modulatory agent may find use in thedisclosed methods. In some instances, the LTA4H modulatory agent is asmall molecule. Naturally occurring or synthetic small moleculecompounds of interest include numerous chemical classes, such as organicmolecules, e.g., small organic compounds having a molecular weight ofmore than 50 and less than about 2,500 daltons. The compounds caninclude functional groups for structural interaction with proteins,particularly hydrogen bonding, and typically include at least an amine,carbonyl, hydroxyl or carboxyl group, preferably at least two of thefunctional chemical groups. The candidate agents may include cyclicalcarbon or heterocyclic structures and/or aromatic or polyaromaticstructures substituted with one or more of the above functional groups.In some embodiments, the LTA4H modulatory agent may be a small organicmolecule that selectively binds to the LTA4H enzyme and reduces (i.e.antagonizes) one or more of its activities including, for example, itsepoxide hydrolase activity and/or its aminopeptidase activity. In somecases, the LTA4H modulatory agent may be a small organic molecule thatselectively binds to the LTA4H enzyme and augments (i.e. acts anagonist) one or more of its activities including, for example, itsepoxide hydrolase activity and/or its aminopeptidase activity. In someembodiments, the LTA4H modulatory agent is a selective or competitiveinhibitor of LTA4H. The LTA4H modulatory agent can also be apharmaceutically acceptable salt thereof of a LTA4H inhibitor.

In certain embodiments, the small molecule LTA4H modulatory agent is apeptide or a peptidomimetic compound. In certain embodiments, thepeptide or peptidomimetic compound comprises one or more of leucine,proline, valine, norvaline, isoleucine, norleucine, methionine andarginine. In certain embodiments, the LTA4H modulatory agent is apeptidomimetic derivative comprising a hydroxamic acid group. In certainembodiments, the LTA4H modulatory agent is a heterocyclic compound.Non-limiting examples of heterocyclic compounds include a piperadinederivative, a piperazine derivative, an oxazole derivative, a thiozolederivative, an imidazole derivative, a pyridine derivative, a pyrimidinederivative, a benzoxazole derivative, a benzothiazole derivative, abenzoimidazole derivative, a thiazolopyridine derivative, athiazolopyrazine derivative, a diazabicyclo[2.2.1]heptane derivative, abenzodioxane derivative, and an arylpyrazole derivative. In certainembodiments, the LTA4H modulatory agent is an aryl compound. In somecases, the aryl compound is a stilbenoid derivative (e.g., a resveratrolderivative). In some cases, the LTA4H modulatory agent is an aryl orbiaryl substituted heterocycle derivative. In will be understood thatany convenient small molecule LTA4H modulatory agent may find use in thesubject methods.

In certain embodiments, the LTA4H modulatory compound is a peptidederivative. In certain embodiments the LTA4H modulatory agent isdescribed by the formula (I):

where:

R¹ is selected from alkyl, substituted alkyl, cycloalkanoalkyl, phenyl,substituted phenyl, benzyl, substituted benzyl; and

R² is selected from hydrogen, alkyl, substituted alkyl, hydroxylalkyl,mercaptoalkyl, carboxyamidoalkyl, alkoxyalkyl, alkylmercaptoalkyl,carboxylalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl,amidinealkyl, substituted amidinealkyl, or a pharmaceutically acceptablesalt, or solvate thereof.

In some embodiments, R¹ is a benzyl group or a substituted benzyl groupand R² is an isobutyl group. In certain embodiments, R¹ a benzyl group,or a substituted benzyl group and R² is —CH₂CH₂CH₂NHC(═NH)NH₂. Incertain cases, the compound of formula (I) is a racemate. In certaincases, the compound of formula (I) is an enantiomer thereof. In certaincases, the configuration of the compound is (2S,3R,2′R), (2S,3S,2'S) or(2S,3S,2′R).

In certain embodiments, the compound of formula (I) is selected from(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-leucine,(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-leucine,(2S,3R)-3-amino-2-hydroxy-4-p-nitrophenylbutanoyl-(S)-leucine,(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-valine,(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-norvaline,(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-methionine,(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-isoleucine,(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(R)-norleucine,(2RS,3RS)-3-amino-2-hydroxy-4-p-chlorophenylbutanoyl-(S)-leucine,(2RS,3RS)-3-amino-2-hydroxy-4-o-chlorophenylbutanoyl-(S)-leucine,(2RS,3RS)-3-amino-2-hydroxy-4-p-methylphenylbutanoyl-(S)-leucine,(2S,3R)-3-amino-2-hydroxy-4-p-aminophenylbutanoyl-(S)-leucine,(2RS,3RS)-3-amino-2-hydroxy-4-hydroxyphenylbutanoyl-(S)-leucine,(2S,3R)-3-amino-2-hydroxy-4-p-hydroxyphenylbutanoyl-(S)-leucine.

In certain embodiments, the compound of formula (I) is selected from(2S,3R)-3-amino-2-hydroxyl-4-phenylbutanoyl-(S)-arginine,(2S,3R)-3-amino-2-hydroxy-4-p-hydroxyphenyl-butanoyl-(S)-arginine,(2RS,3RS)-3-amino-2-hydroxy-4-p-methylphenyl-butanoyl-(S)-arginine.

In certain embodiments, the compound of formula (I) is the compound knowas ubenimex (bestatin), which has the following structure:

Ubenimex analogs and derivatives useful in the methods of the inventioninclude LTA4H inhibitor compounds described in U.S. Pat. Nos. 4,185,156;4,189,604; 4,370,318; and 4,474,764, and G.B. Pat. Nos. 1,510,477,1,510,323, each of which is incorporated herein by reference.

In certain embodiments, the LTA4H modulatory compound is apeptiodomietic derivative. In certain cases, the peptiodomieticderivative comprises a hydroxamic acid group. In certain embodiments theLTA4H modulatory agent is described by the formula (II):

where:

R⁹ is selected from hydrogen, hydroxy, amino, methyl, andthrifluoromethyl;

R¹⁰ is R_(10a)—(X)_(n)-(ALK)-, wherein R^(10a) is selected fromhydrogen, a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl,or heterocycle group, any of which may be unsubstituted or substitutedby (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy, mercapto, (C₁-C₆)alkylthio,amino, trifluoromethyl, cyano, nitro, —COOH, —CONH₂, —COOR^(A),—NHCOR^(A), —CONHR^(A), —NHR^(A), —NR^(A)R^(B), or CONR^(A)R^(B) whereinR^(A) and R^(B) are independently a (C₁-C₆)alkyl group;

ALK represents a straight or branched divalent C₁-C₆ alkylene, C₂-C₆alkenylene, C₂-C₆ alkynylene radical, and may be interrupted by one ormore non-adjacent —NH—, —O— or —S— linkages;

X represents —NH—, —O— or —S—, and

n is 0 or 1;

R is selected from hydrogen or C₁-C₆ alkyl;

R¹¹ is a characterizing group of a natural or non-natural amino acid inwhich any functional groups may be protected; and

R₄ represents an ester or thioester group,

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In certain embodiments, the compound of formula (II) is selected from,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid cyclopentyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid benzyl ester,2S-{2R-[1S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]-4-methyl-pentanoylamino}-3-phenyl-propionicacid isopropyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-4-methyl-pentanoicacid cyclopentyl ester,2S-{2R-[1S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]-4-methyl-pentanoylamino}-3-phenyl-propionicacid isopropyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid methyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid ethyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid isopropyl ester, 3R-(2-Phenyl-1S-methylcarboxy-ethylcarbamoyl)-2S,5-dimethylhexanohydroxamic acid,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenyl-propionicacid tert-butyl ester,2S-(2R-Hydroxycarbamoylmethyl-4-methyl-pentanoylamino)-3-phenyl-propionicacid isopropyl ester,2S-[2R—(S-Hydroxy-hydroxycarbamoyl-methyl)-4-methyl-pentanoytamine]-3-phenyl-propionicacid isopropyl ester,2S-[2R-(1S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3-phenyl-propionicacid isopropyl ester,2S-(2R-Hydroxycarbamoylmethyl-octanoylamino)-3-phenyl-propionic acidisopropyl ester,2S-[2R—(S-Hydroxy-hydroxycarbamoyl-methyl)-4-methyl-pentanoylamino]-3-phenyl-propionicacid cyclopentyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3S-methyl-pentanoicacid cyclopentyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid 2-methoxy-ethyl ester,2S-[2R-(1S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3-phenyl-propionicacid 2-methoxy-ethyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hexanoylamino)-3,3-dimethyl-butyricacid 2-methoxy-ethyl ester,2S-[2R—(S-Hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3-phenyl-propionicacid isopropyl ester,2S-[2-R-(1S-Hydroxycarbamoyl-ethyl)-4-methyl-pentanoylamino]-3,3-dimethyl-butyricacid 2-methoxy-ethyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyricacid 2-methoxy-ethyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hexanoylamino)-3-phenylpropionicacid isopropyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyricacid isopropyl ester,2R-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid isopropyl ester,2S-[2R—(S-Hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3-dimethyl-butyricacid isopropyl ester,2S-{(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoyl)-methyl-amino)-3-phenylpropionicacid isopropyl ester,3-Cyclohexyl-2S-(3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-propionicacid cyclopentyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid 1-methyl-piperidin-4-yl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid 1-ethyl-propyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid 1S-methyl-butyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid cyclohexyl ester,2S-{2R-[1S-Hydroxycarbamoyl-2-(thiophen-2-ylsulphanyl)-ethyl]-4-methyl-pentanoylamino}-3,3-dimethyl-butyricacid isopropyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid 1 R-methyl-butyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-phenylpropionicacid tetrahydro-furan-3(R,S)-yl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3,3-dimethyl-butyricacid cyclopentyl ester,2S-[2R-(1S-Cyclopentyl-hydroxycarbamoyl-methyl)-4-methyl-pentanoylamino]-3-phenyl-propionicacid cyclopentyl ester,2S-[2R-(1S-Hydroxy-hydroxycarbamoyl-methyl)-pent-4-ynoylamino]-3-phenylpropionicacid cyclopentyl ester,2S-(3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-3-pyridin-3-yl-propionicacid cyclopentyl ester,3-tert-Butoxy-2S-(3S-hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-propionicacid cyclopentyl ester,2S-3S-Hydroxycarbamoyl-2R-isobutyl-hex-5-enoylamino)-2-phenylethanoicacid cyclopentyl ester,2S-[5-(2-Chlorophenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyl)-pent-4-ynoylamino]-3-phenylpropionicacid cyclopentyl ester, and2S-(3S-Hydroxycarbamoyl-2R-isobutyl-6-phenyl-hex-5-enoylamino)-3-phenyl-propionicacid cyclopentyl ester, and pharmaceutically acceptable salts, hydratesand esters thereof.

In certain embodiments, the compound of formula (II) is the compoundknown as tosedostat (CHR-2797), which has the following structure:

In certain cases, tosedostat is converted intracellularly into an activeform, known as CHR79888, which has the following structure:

Tosedostat analogs and derivatives useful in the methods of theinvention include compounds described in U.S. Pat. Nos. 6,462,023,5,861,436; and 6,545,051; and International Patent Application Nos.WO1999046241A1; and WO2000044373A1.

In certain embodiments, the LTA4H modulatory agent is a heterocycliccompound. In some cases, the heterocyclic compound is a benzoxazolederivative, a benzothiazole derivative, or a benzoimidazole derivative.In certain embodiments the LTA4H modulatory agent is described by theformula (III):

where:

X is selected from the group consisting of NR⁵a, O, and S, with R^(5a)being one of H and CH₃;

Y is selected from the group consisting of CH₂, and O;

R⁵ is selected from the group consisting of H, OCH₃, Cl, F, Br, I, OH,NH₂, CN, CF₃ and CH₃;

R⁶ is H or F; and

R³ and R⁴ are each independently selected from the group consisting of:

-   -   A) H, C1-7alkyl, C3-7alkenyl, wherein the carbon in said alkenyl        that is attached to the nitrogen member has only single bonds,        C3-7alkynyl, wherein the carbon in said alkynyl that is attached        to the nitrogen member has only single bonds, C3-7cycloalkyl        optionally benzofused, C5-7cycloalkenyl,        —C3-7cycloalkylC1-7alkyl, —C1-7alkylC3-7cycloalkyl and phenyl,        wherein each of the substituents A) is independently substituted        with 0, 1, or 2 R^(Q), and each of said R^(Q) is a substituent        at a carbon member that is at least one carbon member removed        from the nitrogen member;

B) a substituent HetR^(a);

C) —C1-7alkylC(O)R^(x), optionally substituted with CH₂R^(Ar) orCH₂R^(Ar′);

D) —C2-5alkylC(O)R^(x), wherein two valence allowed carbon members inthe C2-5alkyl of said C2-5alkylC(O)R^(x) are part of a saturatedC3-6carbocycle;

E) —C2-5alkylOH wherein two valence allowed carbon members in theC2-5alkyl of said —C2-5alkylOH are part of a saturated C3-6carbocycle;

F) —C0-4alkylphenyl, wherein the phenyl in said —C0-4alkylphenyl isfused at two adjacent carbon members in said phenyl to R^(f), or isbenzofused;

G) —C0-4alkylAr⁶, where Ar⁶ is a 6-membered heteroaryl having a carbonmember point of attachment and having one or two —N=heteroatom members,and benzofused;

H) —C0-4alkylAr⁵, where Ar⁵ is a 5-membered heteroaryl, having oneheteroatom member selected from the group consisting of O, S, and>NR^(Y), and having 0 or 1 —N=additional heteroatom member, optionallycontaining two carbonyl groups, and optionally benzofused;

I) —C1-4alkylAr⁵′, where Ar⁵′ is a 5-membered heteroaryl containing 3 or4 nitrogen members, optionally substituted with RY, and having a valenceallowed site as a point of attachment;

J) —C0-4alkylAr⁶⁶, where Ar⁶⁶ is a C0-4alkyl-attached phenyl fused atvalence allowed sites to a 6-membered heteroaryl, wherein said6-membered heteroaryl has one or two —N=heteroatom members;

K) —C0-4alkylAr⁶⁵, where Ar⁶⁵ is a C0-4alkyl-attached phenyl fused atvalence allowed sites to a 5-membered heteroaryl, said 5-memberedheteroaryl having one heteroatom member selected from the groupconsisting of O, S, and >NR^(Y), and said 5-membered heteroaryl having 0or 1 additional heteroatom member which is —N═;

L) one of 2-(4-ethyl-phenoxy)-benzothiazole,2-(4-ethyl-phenoxy)-benzooxazole, and2-(4-ethyl-phenoxy)-1H-benzoimidazole; and

M) SO₂Cl₄alkyl;

alternatively R² and R³ are taken together with the nitrogen to whichthey are attached to form a heterocyclic ring that contains at least oneheteroatom member that is said attachment nitrogen, said heterocyclicring being selected from the group consisting of:

i) a 4-7 membered heterocyclic ring HetR^(b), said 4-7 memberedheterocyclic ring HetR^(b) having one heteroatom member that is saidattachment nitrogen, and being substituted with 0, 1, or 2 substituentsat the same or at different substitution members, said substituentsbeing selected from the group consisting of —RY, —CN, —C(O)R^(Y),—C₀₋₄alkylCO₂R^(Y), —C₀₋₄alkylC(O)CO₂R^(Y), —C₀₋₄alkylOR^(Y),—C₀₋₄alkylC(O)NR^(Y)R^(Z), —C₀₋₄alkylNR^(Y)C(O)R^(Z), —C(O)NR^(Z)OR^(Y),—C₀₋₄alkylNR^(Y)C(O)CH₂OR^(Y), —C₀₋₄alkylNR^(Y)C(O)CH₂C(O)R^(Y),—C₀₋₄alkylNR^(Y)CO₂R^(Y), —C₀₋₄alkylNR^(Y)C(O)NR^(Y)R^(Z),—C₀₋₄alkylNR^(Y)C(S)NR^(Y)R^(Z), —NR^(Y)C(O)CO₂R^(Y), —NR^(Y)R^(Z),—C₀₋₄alkylNR^(W)SO₂R^(Y), 1,3-dihydro-indol-2-one-1-yl,1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl,1-R^(Y)-1H-tetrazol-5-yl, R^(Y)-triazolyl, 2-R^(Y)-2H-tetrazol-5-yl,pyrrolidine-2-thion-1-yl, piperidine-2-thion-1-yl,—C₀₋₄alkylC(O)N(R^(Y))(SO₂R^(Y)), —C₀₋₄alkylN(R^(Y))(SO₂)NR^(Y)R^(Y),—C₀₋₄alkylN(R^(Y))(SO₂)NR^(Y)CO₂R^(Y), halo,

ii) a 5-7 membered heterocyclic ring HetR^(c), said 5-7 heterocyclicring HetR^(c) having one additional heteroatom member separated fromsaid attachment nitrogen by at least one carbon members, said additionalheteroatom member being selected from the group consisting of O,S(═O)₀₋₂, and >NR^(M), said 5-7 membered heterocyclic ring HetR^(c)having 0 or 1 carbonyl members, and being substituted with 0, 1, or 2substituents at the same or at different carbon substitution members,said substituents being selected from the group consisting of—C(O)R^(Y), —CO₂R^(Y)—C₃ 4alkylCO₂R^(Y) and R^(Z);

iii) one of imidazolidin-1-yl, 2-imidazolin-1-yl, pyrazol-1-yl,imidazol-1-yl, 2H-tetrazol-2-yl, 1H-tetrazol-1-yl, pyrrol-1-yl,2-pyrrolin-1-yl, and 3-pyrrolin-1-yl, wherein each of said2H-tetrazol-2-yl and 1H-tetrazol-1-yl is substituted at the carbonmember with 0 or 1 of —C₀₋₄alkylR^(Z), —C₀₋₄alkylSR^(Y),—C₀₋₄alkylCO₂R^(Y), and substituent HetR^(a); and

iv) one of 1,2,3,4-tetrahydro-quinolin-1-yl,1,2,3,4-tetrahydro-isoquinolin-2-yl, indol-1-yl, isoindol-2-yl,indolin-1-yl, benzimidazol-1-yl, 2,8-diaza-spiro[4.5]decan-1-one-8-yl,4-{[(2-tert-butoxycarbonylamino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl,4-{[(2-amino-cyclobutanecarbonyl)-amino]-methyl}-piperidin-1-yl,3,9-diaza-spiro[5.5]undecane-3-carboxylic acid-9-yl tert-butyl ester,4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-8-yl, and4-oxo-1,3,8-triaza-spiro[4.5]dec-8-yl;

wherein

substituent HetR^(a) is a 4-7 membered heterocyclic ring having a carbonmember point of attachment and containing a member >NR^(M) as aheteroatom member, and said heteroatom member being separated from saidcarbon member point of attachment by at least 1 additional carbonmember;

R^(K) is selected from the group consisting of H, —C₁₋₄alkyl,—C₀₋₄alkylR^(Ar) each optionally substituted with 1, 2, or 3substituents R^(N);

R^(L) is selected from the group consisting of —CO₂R^(S) and—C(O)NR^(S)R^(S′);

R^(M) is selected from the group consisting of R^(Z), indol-7-yl,—SO₂R^(Y), —C₃₄alkylCO₂R^(Y), CO₂R^(Y), —C(O)NR^(Z)OR^(Y), —C(O)R^(Y),—C(O)C₁ 4alkylOR^(Y), —C₀₋₄alkylC(O)NR^(S)R^(S′),—C₀₋₄alkylC(O)CO₂R^(Y), 1,3-dihydro-indol-2-one-1-yl,1,3-dihydro-benzoimidazol-2-one-1-yl, tetrazol-5-yl,1-R^(Y)-1H-tetrazol-5-yl,

R^(Y)-triazolyl, 2-R^(Y)-2H-tetrazol-5-yl and—C₀₋₄alkylC(O)N(R^(Y))(SO₂R^(Y)), each optionally substituted with 1, 2or 3 substituents R^(N);

R^(N) is selected from the group consisting of OCH₃, Cl, F, Br, I, OH,NH₂, CN, CF₃, CH₃, OC(O)CH₃, and NO₂; R^(P) is selected from the groupconsisting of R^(Y), —C₂₋₄alkylOR^(Y), R^(Ar), —C₁₋₂alkylCO₂R^(Y),—C₁₋₂alkylCONR^(S)R^(S′), indol-7-yl, and —SO₂C₁₋₄alkyl;

R^(Q) is selected from the group consisting of fluoro, chloro, bromo,iodo, trifluoromethyl, trichloromethyl, —CN, —C₁₋₄alkyl,—C₀₋₄alkylR^(Ar), —C₀₋₄alkylR^(Ar′), —C₀₋₄alkylOR^(Y),—C₀₋₄alkylCO₂R^(Y), —C₀₋₄alkylNR^(Y)R^(Z), —C₀₋₄alkylNR^(Y)COR^(Y),—C₀₋₄alkylNR^(Y)CONR^(Y)R^(Z), —C₀₋₄alkylNR^(Y)SO₂R^(Y), and—C₀₋₄alkylSR^(Y);

R^(S) and R^(S′) are independently selected from the group consisting ofH, —C₁₋₄alkyl, and —C₀₋₄alkylphenyl; alternatively, R^(S) and R^(S′) aretaken together with the nitrogen member to which said R^(S) and R^(S′)are attached to form a 4-7 membered heterocyclic ring having 0 or 1additional heteroatom member selected from the group consisting of O, S,and >NR^(Y), provided that said additional heteroatom member isseparated by at least two carbon members from said nitrogen member towhich said R^(S) and R^(S′) are attached, and provided that where R^(Y)is C₀₋₄alkylR^(Ar), then R^(Ar) is not substituted with R^(L); R^(W) isselected from the group consisting of R^(Y), and —C₃₋₇cycloalkyl;

R^(X) is selected from the group consisting of —OR^(Y), —NR^(Y)R^(Z),—C₁₋₄alkyl, and —C₀₋₄alkylR^(Ar);

R^(Y) is selected from the group consisting of H, —C₁₋₄alkyl,—C₀₋₄alkylR^(Ar) and —C₀₋₄alkylR^(Ar′),

each optionally substituted with 1, 2, or 3 substituents R^(N);

R^(Z) is selected from the group consisting of R^(Y), —C₂₋₄alkylOR^(Y),—C₁₋₂alkylCO₂R^(Y), —C₁₋₂alkylC(O)NR^(S)R^(S′), and—C₂₋₄alkylNR^(S)R^(S′);

when R^(Y) and R^(Z) are attached to a nitrogen member, R^(Y) and R^(Z)are selected as defined above, or R^(Y) and R^(Z) are taken togetherwith the R^(Y)— and R^(Z)— attached nitrogen member to form a 4-7membered heterocyclic ring HetR^(d) having 0 or 1 additional heteroatommembers selected from the group consisting of O, S, and >NR^(M), said4-7 membered heterocyclic ring HetR^(d)having 0 or 1 carbonyl members,and said 4-7 membered heterocyclic ring HetR^(d) having 0 or 1 valenceallowed carbon members substituted with at least one of R^(M), —CO₂H,and —C₀₋₁ alkylOR^(Y);

R^(Ar) is a moiety with a carbon member attachment point and said moietyis selected from the group consisting of phenyl, pyridyl, pyrimidyl, andpyrazinyl, wherein each valence allowed carbon member in each of saidmoieties is independently substituted with at least one of 0, 1, 2 or 3R^(N), and 0 or 1 R^(L);

R^(Ar′) is a 3-8 membered ring, having 0, 1 or 2 heteroatom membersselected from the group consisting of O, S, N, and >NR^(Y), having 0, 1,or 2 unsaturated bonds, having 0 or 1 carbonyl members, wherein eachvalence allowed member in each of said rings is independentlysubstituted with 0, 1, or 2 R^(K); and

R^(f) is a linear 3-to 5-membered hydrocarbon moiety having 0 or 1unsaturated carbon-carbon bonds and having 0 or 1 carbonyl members.

In some embodiments, the compound of formula (III) is selected from,2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzooxazole,(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]ethyl}piperidin-4-yl)-methanol,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol, 2-[4(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine,(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol,1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4 phenyl-piperidin-4-ol,1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-4-benzyl-piperidin-4-ol,2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzooxazole,3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclohexyl-ethyl-amine,1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-piperidin-4-ol,1-{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-2-hydroxy-propyl}-4-phenyl-piperidin-4-ol,1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylicacid ethyl ester,2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzooxazole,{3-[4-(Benzooxazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine,2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine,2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzooxazole,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol,{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidine-4-carbonitrile,1-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-yl)-ethanone,2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ol,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl-4-(4-bromo-phenyl)-piperidin-4-ol,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluoromethyl-phenyl)piperidin-4-ol,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol,2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-methyl-amine,{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-cyclopropylmethyl-propyl-amine,{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-butyl-ethyl-amine,2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-ethanol,2-{4-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-phenoxy}-benzooxazole,(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-3-yl)-methanol,2-({2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-propyl-amino)-ethanol,2-[4-(2-Azetidin-1-yl-ethoxy)-phenoxy]benzoxazole,N-(1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide,1-{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-piperidine-3-carboxylicacid ethyl ester,2-{4-[3-(4-Phenyl-piperidin-1-yl)-propoxy]-phenoxy}-benzooxazole,1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol,{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzooxazole,2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzooxazole,2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine,{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,1-{2-[4-(Benzooxazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid methyl ester,1-{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-4-phenyl-piperidin-4-ol,2-[4-(3-Piperidin-1-yl-propyl)-phenoxy]-benzooxazole,{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-dibutyl-amine,{3-[4-(Benzooxazol-2-yloxy)-phenyl]-propyl}-cyclopropylmethyl-propyl-amine,1-[4-(Benzooxazol-2-yloxy)-phenoxy]-3-pyrrolidin-1-yl-propan-2-ol,1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-4-phenyl-piperidin-4-ol,1-[2-(4-Benzooxazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylicacid amide, 2-(4-Piperidin-1-ylmethyl-phenoxy)-benzooxazole,2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzooxazole, and{2-[4-(Benzooxazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine andpharmaceutically acceptable salts, prodrugs, and solvates thereof of anyof the foregoing compounds.

In some embodiments, the compound of formula (III) is selected from,{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylicacid,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-1-yl-methanone,3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionicacid ethyl ester,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylicacid amide,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one,1′-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4′]bipiperidinyl-2-one,8-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,8-diaza-spiro[4.5]decan-1-one,2-[4-(3-Pyrrolidin-1-yl-propoxy)-phenoxy]-benzothiazole,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylicacid amide,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-methyl-1,3-dihydro-benzoimidazol-2-one,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid methyl ester,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone,1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylicacid methyl ester,3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)-propionicacid, {2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dimethyl-amine,2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-benzothiazole,{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine,2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-benzothiazole,2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-benzothiazole,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol,{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ol,{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-dibutyl-amine,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol,1′-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4′]bipiperidine,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide,1′-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4′]bipiperidinyl-2-one,2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole,2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethyl}-phenoxy)-benzothiazole,1-{3-[4-(Benzothiazol-2-yloxy)-phenoxy]-propyl}-4-phenyl-piperidin-4-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidin-4-ol,2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-benzothiazole,2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-benzothiazole,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-benzothiazole,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid methyl ester,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid amide,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylicacid ethyl ester,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-4-phenyl-piperidine-4-carboxylicacid ethyl ester,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-aceticacid ethyl ester,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-1,3-dihydro-indol-2-one,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-2-phenyl-acetamide,8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,8-diaza-spiro[4.5]decan-1-one,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-ol,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid ethyl ester,1′-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-[1,4′]bipiperidine,2-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenoxy}-benzothiazole,2-(4-{2-[4-(1-Benzyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethoxy}-phenoxy)-benzothiazole,4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester,2-(4-{2-[4-(2-Morpholin-4-yl-ethyl)-piperazin-1-yl]-ethyl}-phenoxy)-benzothiazole,1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidine-4-carboxylicacid amide,1-{1-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-piperidin-4-yl}-pyrrolidin-2-one,1-[4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidine-2-thione,2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-ethanol,2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-1-pyrrolidin-1-yl-ethanone,2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylicacid,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-2-carboxylicacid,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-yl)-aceticacid,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid ethyl ester,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-aceticacid,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-3-yl)-methanol,({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-amino)-aceticacid methyl ester,(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-aceticacid,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-oxo-pyrrolidine-2-carboxylicacid ethyl ester,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-5-oxo-pyrrolidine-2-carboxylicacid,4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-phenol,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-chloro-N-cyclopropyl-benzenesulfonamide,3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropylmethyl-amino)-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-isopropyl-amino)-propionicacid,1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ylamine,3-[{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-(1-methyl-piperidin-4-yl)-amino]-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-benzyl-amino)-propionicacid,3-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-amino)-propionicacid,4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-piperidine-1-carboxylicacid tert-butyl ester,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propionicacid,3-((1-Acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-propionicacid,3-[{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-(1-methyl-piperidin-4-yl)-amino]-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino)-propionicacid,2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-1-pyrrolidin-1-yl-ethanone,(R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-3-carboxylicacid,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one,2-(4-{2-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-ethyl}-phenoxy)-benzothiazole,2-{4-[2-(4-Ethanesulfonyl-piperazin-1-yl)-ethyl]-phenoxy}-benzothiazole,2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methyl-amino)-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopentyl-amino)-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclobutyl-amino)-propionicacid,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-benzyl-amino)-propionicacid,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-(4-hydroxymethyl-piperidin-1-yl)-methanone,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amine,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone,2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-ethanol,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propan-1-ol,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-butyricacid,3-[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amino]-propionicacid,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-butyronitrile,3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-propionicacid,[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-aceticacid,3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazin-1-yl)-phenol,2-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethoxy}-phenoxy)-benzothiazole,2-{4-[2-(5-Piperidin-4-yl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole,(S)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one,2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amine,2-[({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-methyl]-cyclopropanecarboxylicacid ethyl ester,4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperazine-1-carbonyl)-benzoicacid ethyl ester,2-[({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-methyl]-cyclopropanecarboxylicacid,1-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propan-2-ol,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-1,1,1-trifluoro-propan-2-ol,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propionamide,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propane-1,2-diol,2-{4-[2-(5-Phenyl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole,2-{4-[2-(5-Phenyl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole,N-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N-cyclopropyl-2-(2H-tetrazol-5-yl)-acetamide,(S)-3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propan-1-ol,(R)-3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propan-1-ol,2-{4-[2-(5-Methylsulfanyl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazole,2-{4-[2-(5-Methylsulfanyl-tetrazol-1-yl)-ethoxy]-phenoxy}-benzothiazole,2-[4-(2-Tetrazol-2-yl-ethoxy)-phenoxy]-benzothiazole,2-[4-(2-Tetrazol-1-yl-ethoxy)-phenoxy]-benzothiazole,(1R,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylicacid,(1S,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylicacid,(1R,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanol,(1S,2R)-2-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanol,4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-butyricacid, 1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-pyrrolidin-2-one,2-(2-Fluoro-4-piperidin-1-ylmethyl-phenoxy)-benzothiazole,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2-hydroxy-acetamide,1-(2-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-ethyl)-4-hydroxy-pyrrolidin-2-one,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-methanesulfonamide,2-{4-[4-(1H-Tetrazol-5-yl)-piperidin-1-ylmethyl]-phenoxy}-benzothiazole,1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-2-hydroxy-ethanone,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-methanesulfonamide,3-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxazolidin-2-one,4-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-morpholin-3-one,(R)1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one,2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-2-yl)-methanol,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-aceticacid ethyl ester,(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-1H-tetrazol-5-yl)-aceticacid ethyl ester,2-{4-[2-(5-Piperidin-4-yl-tetrazol-2-yl)-ethoxy]-phenoxy}-benzothiazolehydrochloride,7-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-4-spiro-[3-phthalide]-piperidine,1-{3-[4-(Benzothiazol-2-yloxy)-phenyl]-propyl}-piperidine-4-carboxylicacid ethyl ester, 2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylaminehydrochloride,2-(4-{2-[4-(1H-Tetrazol-5-yl)-piperidin-1-yl]-ethoxy}-phenoxy)-benzothiazole,2-(4-Piperidin-1-ylmethyl-phenoxy)-benzooxazole,[4-(Benzothiazol-2-yloxy)-benzyl]-cyclohexyl-ethyl-amine,[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropylmethyl-propyl-amine,1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid amide,1′-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4′]bipiperidinyl-2-one,{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-pyridin-3-yl-methanone,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamic acidtert-butyl ester,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamic acidmethyl ester,N—{C-[[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl]-methylaminosulfonyl}-carbamic acid tert-butyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-sulfamidehydrochloride,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-acetamide,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetic acid, Aceticacid({1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamoyl)-methylester,[2-({1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-carbamoyl)-cyclobutyl]-carbamicacid tert-butyl ester, 2-Amino-cyclobutanecarboxylic acid{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-amidedihydrochloride, 2-(4-Pyrrolidin-1-ylmethyl-phenoxy)-benzothiazole,2-{[4-(Benzothiazol-2-yloxy)-benzyl]-ethyl-amino}-ethanol,2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-ethanol,1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-ethanone,8-[4-(Benzothiazol-2-yloxy)-benzyl]-2,8-diaza-spiro[4.5]decan-1-one,Spiro[isobenzofuran-1(3H), 4′-piperidin]-3-one,1′-[4-(Benzothiazol-2-yloxy)-benzyl](R)-1-[4-(Benzothiazol-2-yloxy)-benzyl]-pyrrolidin-3-ol,2-[4-(2-Methyl-piperidin-1-ylmethyl)-phenoxy]-benzothiazole,[4-(Benzothiazol-2-yloxy)-benzyl]-diethyl-amine,[4-(Benzothiazol-2-yloxy)-benzyl]-butyl-methyl-amine,2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-ethanol,1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-2-yl}-methanol,(R)-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-pyrrolidin-2-yl}-methanol,2-(4-Azetidin-1-ylmethyl-phenoxy)-benzothiazole,1-[4-(Benzothiazol-2-yloxy)-benzyl]-[1,4]diazepan-5-one,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yl}-methanol,1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-3-carboxylic acid amide,9-[4-(Benzothiazol-2-yloxy)-benzyl]-3,9-diaza-spiro[5.5]undecane-3-carboxylicacid tert-butyl ester,2-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-3-yl}-ethanol,cis-4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-cyclohexanecarboxylicacid trifluoromethanesulfonate salt,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone,propane-2-sulfonic acid(1-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-amide,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-aceticmethyl ester,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-benzenesulfonamidetrifluoromethanesulfonate salt,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonyl)-methanesulfonamidetrifluoromethanesulfonate salt,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-oxo-aceticacid trifluoromethanesulfonate salt,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-morpholin-4-yl-methanone,1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-thiophen-2-yl-ethanone,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-3-yl-methanone,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-cyclopropyl-methanone,1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone,1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2,2,2-trifluoro-ethanone,4-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazine-1-carbonyl)-benzoicacid,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-pyridin-4-yl-methanone,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(5-methyl-pyrazin-2-yl)-methanone,(R)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone,(S)-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone,(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-3-yl)-methanone,1-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone,2-[2-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-2-oxo-ethyl]-cyclopentanone,3-(4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazin-1-yl)-propionicacid trifluoromethanesufonate salt,3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-oxazolidin-2-one,4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-morpholin-3-one,4-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-morpholin-3-one,3-(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-oxazolidin-2-one,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid benzyloxy-amide,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-aceticacid,(R)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid hydroxyamide,(S)-1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-4-hydroxy-pyrrolidin-2-one,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-carbamicacid tert-butyl ester,2-{4-[2-(4-Fluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole,2-{4-[2-(4,4-Difluoro-piperidin-1-yl)-ethyl]-phenoxy}-benzothiazole,(R)-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-pyrrolidin-3-ol,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-Formamide,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-urea,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-phenyl-isourea,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-isothiourea,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methanesulfonamide,1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-3-cyano-2-methyl-guanidine,8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,8-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-1,3,8-triaza-spiro[4.5]decane-2,4-dione,(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamicacid tert-butyl ester,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-methyl-acetamide,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-methyl-methanesulfonamide,acetic acid[(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-methyl-carbamoyl]-methylester,N-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-N-acetamide,acetic acid(1-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ylcarbamoyl)-methylester,2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methyl-amino)-3-(1H-imidazol-2-yl)-propionicacid,2-(4-{2-[4-(3-Nitro-pyridin-2-yl)-[1,4]diazepan-1-yl]-ethyl}-phenoxy)-benzothiazole,2-(4-Piperidin-1-ylmethyl-phenoxy)-benzothiazole,1-[4-(Benzothiazol-2-yloxy)-benzyl]-4-phenyl-piperidin-4-ol,1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ol,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanol,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methanesulfonamide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-2-hydroxy-acetamide,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acidmethyl ester,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-urea,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylmethyl}-2,2,2-trifluoro-acetamide,{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-acetic acid,2-[4-(4-Methanesulfonyl-piperazin-1-ylmethyl)-phenoxy]-benzothiazole,1-{4-[4-(Benzothiazol-2-yloxy)-benzyl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone,2-(4-Morpholin-4-ylmethyl-phenoxy)-benzothiazole,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acidphenyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-benzenesulfonamide,3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic acid ethyl ester,3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propionic acid,[(1-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carbonyl)-methyl-amino]-aceticacid ethyl ester,1′-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4′]bipiperidinyl-4-carboxylicacid ethyl ester,1′-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-[1,4′]bipiperidinyl-4-carboxylicacid,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-ethyl-amine,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-2-methyl-propionicacid trifluoromethansulfonic acid salt,2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-ethanol,2-[2-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-ethoxy]-ethanol,3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propan-1-ol,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-(3-tetrazol-2-yl-propyl)-amine,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-(3-pyrrol-1-yl-propyl)-amine,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-butyronitrile,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid (2-cyano-ethyl)-amide,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(2H-tetrazol-5-yl)-propyl]-amine,3-[5-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-yl)-tetrazol-1-yl]-propionitrile,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-[3-(2H-tetrazol-5-yl)-propyl]-amine,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid (2-hydroxy-1,1-dimethyl-ethyl)-amide,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(1H-[1,2,4]triazol-3-yl)-propyl]-amine,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(5-methyl-1H-[1,2,4]triazol-3-yl)-propyl]-amine,{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-[3-(5-phenyl-1H-[1,2,4]triazol-3-yl)-propyl]-amine,2-(4-{2-[4-(1-Methyl-1H-tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole,2-(4-{2-[4-(2-Methyl-2H-tetrazol-5-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole,1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carbonitrile,2-(4-{2-[4-(1H-[1,2,3]Triazol-4-yl)-piperidin-1-yl]-ethyl}-phenoxy)-benzothiazole,4-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-butyric acid ethylester,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-butyricacid ethyl ester,2-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-isoindole-1,3-dione,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}cyclopropylmethyl-amino)-butyricacid,1-(3-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethylamino}-propyl)-pyrrolidin-2-one,N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropylmethyl-propane-1,3-diamine,5-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-pentanoicacid methyl ester,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-acetamide,morpholine-4-carboxylic acid[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-amide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-methanesulfonamide,5-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-pentanoicacid,1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-isopropyl-amino)-propyl]-pyrrolidin-2-one,1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-amino)-propyl]-pyrrolidin-2-one,1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-pyrrolidin-2-one,1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-propyl-amino)-propyl]-pyrrolidin-2-one,4-((1-acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-butyricacid ethyl ester,4-((1-acetyl-piperidin-4-yl)-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-amino)-butyricacid ethyl ester,4-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-methanesulfonyl-amino)-butyricacid,({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-aceticacid,6-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-hexanoicacid ethyl ester,7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-heptanoicacid ethyl ester,6-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-hexanoicacid,7-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-heptanoicacid,N-1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-N1-cyclopropyl-propane-1,3-diamine,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-acetamide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-isobutyramide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}I-cyclopropyl-amino)-propyl]-benzamide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-4-chloro-benzamide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-methanesulfonamide,propane-2-sulfonic acid[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-amidetrifluoromethanesulfonic acid salt,8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoicacid ethyl ester,1-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-3-phenyl-urea,8-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-octanoicacid, tetrahydro-furan-2-carboxylic acid[3-({2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-amide,N-[3-({2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-cyclopropyl-amino)-propyl]-2-hydroxy-acetamide,4-({2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-cyclopropyl-amino)-butyricacid,1-{3-[4-(Benzothiazol-2-yloxy)-benzylamino]-propyl}-pyrrolidin-2-one,1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-methyl-amino}-propyl)-pyrrolidin-2-one,1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-isopropyl-amino}-propyl)-pyrrolidin-2-one,1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-ethyl-amino}-propyl)-pyrrolidin-2-one,[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amine,N-1-[4-(Benzothiazol-2-yloxy)-benzyl]-N1-cyclopropyl-propane-1,3-diamine,N-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-propyl)-isobutyramide,1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-cyclopropyl-amino}-propyl)-3-isopropyl-urea,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-isopropyl-urea,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxalamic acidmethyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-isobutyramide,tetrahydro-furan-2-carboxylic acid{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-4-hydroxy-pyrrolidin-2-one,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-4-hydroxy-pyrrolidin-2-one,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-urea,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-oxalamic acid,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-2-hydroxy-acetamide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]piperidin-4-yl}-2,2,2-trifluoro-acetamide,2-[4-(1,1-Dioxo-1|6-thiomorpholin-4-ylmethyl) phenoxy]-benzothiazole,N-{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-aminosulfonyl}-carbamic acid tert-butyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-acetamide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N,N-dimethylsulfamide,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyl-urea,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-ethyl-thiourea,propane-1-sulfonic acid{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,propane-2-sulfonic acid{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-amide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-sulfamide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-formamide,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acid ethylester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-propionamide,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-butyramide,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-propyl-urea,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acidpropyl ester,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-3-methyl-urea,1-{-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1,3-dimethyl-urea,1-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1-methyl-urea,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-acetamide,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-methyl-carbamicacid methyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-oxalamicacid methyl ester,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N-methyl-oxalamicacid, Guanidine,N-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-N′-hydroxy,{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-carbamic acidisopropyl ester,3-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-1,1-dimethyl-urea,acetic acid{1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidin-4-ylcarbamoyl}-methylester, {1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidin-4-yl}-thiourea,2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-benzothiazole; and2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-benzothiazole andpharmaceutically acceptable salts, prodrugs, and solvates thereof of anyof the foregoing compounds.

In some embodiments, the compound of formula (III) is selected from,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-phenyl-piperidin-4-ol,{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclopropylmethyl-propyl-amine,cyclohexyl-ethyl-{2-[4-(1-methyl-1H-benzoimidazol-2-yloxy)-phenyl]-ethyl}-amine,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-bromo-phenyl)-piperidin-4-ol,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-(4-chloro-phenyl)-piperidin-4-ol,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-4-benzyl-piperidin-4-ol,{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-cyclohexyl-ethyl-amine,2-[4-(2-Pyrrolidin-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,2-[4-(2-Azepan-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-dibutyl-amine,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidin-4-ol,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenyl]-ethyl}-piperidine-4-carboxylicacid methyl ester,{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-cyclohexyl-ethyl-amine,2-{4-[2-(4-Methyl-piperidin-1-yl)-ethoxy]-phenoxy}-1H-benzoimidazole,2-{4-[2-(2-Ethyl-piperidin-1-yl)-ethoxy]phenoxy}-1H-benzoimidazole,2-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole,(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol,1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-ol,2-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole amide,3-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-propyl}-dimethyl-amine,2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenoxy]-1H-benzoimidazole,{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-diethyl-amine,2-[4-(2-Morpholin-4-yl-ethoxy)-phenoxy]-1H-benzoimidazole,2-[4-(2-Piperidin-1-yl-ethyl)-phenoxy]-1H-benzoimidazole,1-(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-pyrrolidin-2-one,(1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidin-4-yl)-methanol;and1-{2-[4-(1H-Benzoimidazol-2-yloxy)-phenoxy]-ethyl}-piperidine-4-carboxylicacid ethyl ester and pharmaceutically acceptable salts, prodrugs, andsolvates thereof of any of the foregoing compounds.

In certain embodiments, the compound of formula (III) is the compoundknown as JNJ26993135, which has the following structure:

JNJ26993135 analogs and derivatives useful in the methods of theinvention include the LTA4H inhibitor compounds described in US PatentApplication Publication Nos. 20080194630A1; 20050043379A1 and20050043378A1, each of which is incorporated herein by reference.

In certain cases, the LTA4H modulatory agent is a heterocyclic compoundcomprising a thiazolopyridine group. In certain embodiments the LTA4Hmodulatory agent is described by the formula (IV):

where:

X⁴, X⁵, X⁶, and X⁷ are defined as one of the following a) and b):

a) one of X⁴, X⁵, X⁶ and X⁷ is N and the others are CR^(a); where eachR^(a) is independently H, methyl, chloro, fluoro, or trifluoromethyl;andb) each of X⁴ and X⁷ is N and each of X⁵ and X⁶ is CH;

each of R⁷ and R⁸ is independently H, —(CH₂)₂₋₃OCH₃, —CH₂C(O)NH₂,—(CH₂)₃NH₂, —(CH₂)₁₋₂CO₂H, —CH₂CO₂CH₂CH₃, benzyl,3-(2-oxo-pyrrolidin-1-yl)-propyl, 1-acetyl-azetidin-3-ylmethyl,monocyclic cycloalkyl, 1-methyl-4-piperidinyl, or —C₁₋₄alkylunsubstituted or substituted with phenyl, monocyclic cycloalkyl, OH, orNR^(b)R^(c)C; where R^(b) and R^(c) are each independently H, —C(O)CH₃,or C₁₋₄alkyl, or R^(b) and R^(c) taken together with the nitrogen towhich they are attached form a saturated monocyclic heterocycloalkylring; or

R⁷ and R⁸ taken together with the nitrogen to which they are attachedform:

i) a saturated monocyclic heterocycloalkyl ring, optionally fused to aphenyl ring, and unsubstituted or substituted with one or two R^(d)substituents; where each R^(d) substituent is independently C₁₋₄alkylunsubstituted or substituted with —OH; —OH; ═O; —(CH₂)O₀₋₂N(CH₃)₂; —CF₃;halo; —CO₂C₁₋₄alkyl; —(CH₂)O₂CO₂H; —C(O)NH₂; phenyl; benzyl;morpholin-4-yl; pyridyl; pyrimidinyl; 1-piperidyl; phenoxy;2-oxo-pyrrolidin-1-yl; 4-hydroxy-2-oxo-pyrrolidin-1-yl;—C(O)NR^(f)C₁₋₄alkyl; —C(O)NHC(CH₃)₀₋₂CH₂OH; —O-pyridinyl,—O-pyrimidinyl; —S-phenyl; (4-methylphenyl)sulfanyl; —S— pyridinyl;—C(O)—C₁₋₄alkyl; —C(O)-saturated monocyclic cycloalkyl;—C(O)—(CH₂)₀₋₁-2-thiophene-yl; —C(O)-2-furanyl; —C(O)-4-morpholinyl;—C(O)-pyridyl; —C(O)-1-pyrrolidinyl; —C(O)-phenyl optionally substitutedwith a chloro; —C(O)-1-piperazinyl optionally substituted withC₁₋₄alkyl; —(CH₂)₀₋₁NHC(O)—C₁₋₄alkyl; —NHC(O)-saturated monocycliccycloalkyl; —NHS(O)(O)CH₃; —NHC(O)—CH₂OCH₃; —NHC(O)-pyridinyl; or—NHC(O)-2-thiophene-yl, where each phenyl in R^(d) is unsubstituted orsubstituted with —CF₃, halo, or methoxy; or

ii) one of the following moieties:

where R^(e) is —C₁₋₄alkyl, C(O)C₁₋₄alkyl, —SO₂CH₃, —C(O)CH₂NH₂, orC(O)NH₂; R^(f) is H or —CH₃; and A is —CH₂—, —CH₂CH₂—, or —OCH₂CH₂—.

In some embodiments, the compound of formula (IV) is selected from,2-(4-{2-[4-(Pyrimidin-2-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-{4-[2-(1,3-Dihydro-2H-isoindol-2-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[4-(Phenylsulfanyl)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[4-(Pyridin-3-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,4-Pyridin-2-yl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,2-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-1,2,3,4-tetrahydroisoquinoline,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-1,2,3,4-tetrahydroquinoline,2-{4-[2-(4-Phenoxypiperidin-1-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-[4-(2-Pyrrolidin-1-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(2-Piperidin-1-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(2-Morpholin-4-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[4-(Pyridin-2-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[4-(Pyridin-4-yloxy)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,(1S,4S)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,2-{4-[2-(4-Benzylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxamide,1-(1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-yl)pyrrolidin-2-one,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol,2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,N-Benzyl-N-methyl-2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethanamine,(1S,4S)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,1-(1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-yl)pyrrolidin-2-one,4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-ol,2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3yl]acetamide,meso-1-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]urea,meso-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxamide,meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(Ethyl{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}amino)ethanol,N-(Cyclopropylmethyl)-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}propan-1-amine,(1R)—N-Methyl-1-phenyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}ethanamine,2-[4-(2-Morpholin-4-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(2-Piperidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(2-Pyrrolidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-ol,2-{4-[2-(4-Benzylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol,2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidine-4-carboxamide,2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,meso-1-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]urea,2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,(1R,4R)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,1-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperidine-4-carboxylicacid,{-4-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]morpholin-2-yl}methanol,1-{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrolidin-2-one,2-[4-(Pyrrolidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-[4-(Morpholin-4-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,2-(4-{[(3R)-3-Fluoropyrrolidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[(3S)-3-Methylmorpholin-4-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}propan-2-ol,2-(4-{[(2S)-2-Methylpiperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-Piperidin-1-yl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]ethanamine,2-(4-{[4-(Trifluoromethyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-{4-[(3,3-Difluoropyrrolidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,(3R)-1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]pyrrolidin-3-ol,{1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}methanol,2-{4-[(4-Fluoropiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-{4-[(4-Methylpiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Pyridin-3-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Pyrimidin-2-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxamide,4-Pyridin-2-yl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-ol,2-{4-[(4-Benzylpiperidin-1-yl)methyl]phenoxy}[13]thiazolo[4,5-b]pyridine,1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol,4-(4-Chlorophenyl)-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-ol,4-Phenyl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-ol,(1S,4S)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,meso-2-(4-{[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,{(2S)-1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]pyrrolidin-2-yl}methanol,meso-N-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}urea,N-Ethyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]ethanamine,meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,meso-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-6-methyl[1,3]thiazolo[4,5-b]pyridine,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-6-chloro[1,3]thiazolo[4,5-b]pyridine,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-7-methyl[1,3]thiazolo[4,5-b]pyridine,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-5-methyl[1,3]thiazolo[4,5-b]pyridine,1-{(1S,4S)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethenone,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-6-fluoro[1,3]thiazolo[4,5-b]pyridine,6-Fluoro-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,Ethyl1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylate,1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylicacid,2-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-[4-(2-{4-[(4-Chlorophenyl)sulfanyl]piperidin-1-yl}ethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,1-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-ol,7-Methyl-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-b]pyridine,N-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}cyclopropanamine,2-Methyl-N-[1-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)piperidin-4-yl]propenamide,meso-2-{4-[2-(3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl)ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyridine,meso-1-[(3-exo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]urea,7-Methyl-2-(4-{2-[4-(pyridin-4-ylcarbonyl)piperazin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,6-Methyl-2-(4-{2-[4-(morpholin-4-ylcarbonyl)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{2-[5-(Cyclobutylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]ethoxy}phenoxy)-7-methyl[1,3]thiazolo[4,5-b]pyridine,6-Chloro-2-(4-{2-[4-(furan-2-ylcarbonyl)piperazin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-3-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,N-[1-(2-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)piperidin-4-yl]acetamide,1-{3-[(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)(methyl)amino]propyl}pyrrolidin-2-one,1-(2-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-4-pyridin-2-ylpiperidin-4-ol,meso-(3-endo)-8-acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,N-Methyl-2-(methyloxy)-N-[2-({4-[(7-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}oxy)ethyl]ethanamine,meso-2-{[4-({2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}oxy)phenyl]oxy}[1,3]thiazolo[4,5-b]pyridine,N-[1-(2-{[4-[1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]oxy}ethyl)piperidin-4-yl]methanesulfonamide,N-Methyl-1-[2-({4-[(7-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}oxy)ethyl]piperidine-4-carboxamide,meso-N-{(3-endo)-8-[2-({4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}oxy)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}glycinamide,meso-3-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,N,N-Dimethyl-1-({4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}methyl)piperidine-4-carboxamide,N-Ethyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)butan-1-amine,meso-(3-exo)-8-Acetyl-N-({4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}methyl)-8-azabicyclo[3.2.1]octan-3-amine,meso-N-[(3-endo)-8-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl}-8-azabicyclo[3.2.1]oct-3-yl]methanesulfonamide,2-({4-[(4-Cyclobutylpiperazin-1-yl)methyl]phenyl}oxy)-6-methyl[1,3]thiazolo[4,5-b]pyridine,meso-2-[(4-{[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]methyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyridine,6-Chloro-2-[(4-{[4-(2-thienylcarbonyl)piperazin-1-yl]methyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyridine,6-Chloro-2-[(4-{[5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]methyl}phenyl)oxy][,3]thiazolo[4,5-b]pyridine,6-Chloro-2-{[4-(thiomorpholin-4-ylmethyl)phenyl]oxy}[1,3]thiazolo[4,5-b]pyridine,(1R,4R)-5-({4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,(1S,4S)-5-({4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,6-Chloro-2-[(4-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]ethyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyridine,6-Methyl-2-[(4-{2-[4-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyridine,meso-3-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,meso-7-Methyl-2-(4-{[3-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,N-(1-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidin-4-yl)pyridine-4-carboxamide,meso-2-(4-{2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}phenoxy)-7-methyl[1,3]thiazolo[4,5-b]pyridine,meso-3-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,meso-8-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxamide,meso-2-(4-{2-[8-Acetyl-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-2-(4-{2-[3-(Methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-(3-exo)-8-Acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,meso-(3-exo)-8-Acetyl-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]octan-3-amine,2-Methoxy-N-(1-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidin-4-yl)acetamide,2-{4-[(4-tert-Butylpiperidin-1-yl)methyl]phenoxy}-6-chloro[1,3]thiazolo[4,5-b]pyridine,N-(1-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidin-4-yl)thiophene-2-carboxamide,1′-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-1,4′-bipiperidine,3-(4-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl}piperazin-1-yl)propanoicacid,6-Methyl-2-(4-{[4-(piperazin-1-ylcarbonyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-3-(2-{4-[(6-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,meso-(3-exo)-8-Acetyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-8-azabicyclo[3.2.1]octan-3-amine,meso-(3-exo)-8-Acetyl-N-methyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-8-azabicyclo[3.2.1]octan-3-amine,N2-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-N2-methylglycinamide,meso-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]octane-3-carboxylicacid,6-Chloro-2-(4-{2-[5-(1-methylethy)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,N-Methyl-N-(2-{4-[(6-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenoxy}ethyl)-beta-alanine,N-(2-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]phenyl}ethyl)-N,1-dimethylpiperidin-4-amine,6-Methyl-2-{4-[2-(4-pyridin-2-ylpiperidin-1-yl)ethyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,1-(1-Acetylazetidin-3-yl)-N-{4-[(6-chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-N-methylmethanamine,meso-(3-exo)-3-{[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]amino-8-azabicyclo[3.2.1]octane-8-carboxamide,2-[4-(2-{4-[(4-Methylphenyl)sulfanyl]piperidin-1-yl}ethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine,1′-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-1,4′-bipiperidine,2-{4-[(4-Morpholin-4-ylpiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,N,N-Dimethyl-2-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-2-yl}ethanamine,N,N-Dimethyl-1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-amine,2-{4-[(4-Phenoxypiperidin-1-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Pyridin-2-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Pyridin-4-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Pyridin-2-ylsulfanyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[4-(Phenylsulfanyl)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,2-(4-{[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,(1R,4R)-5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-b]pyridine,(1R,4R)-5-{2-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,(4R)-4-Hydroxy-1-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrolidin-2-one,(4R)-4-Hydroxy-1-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-yl)pyrrolidin-2-one,N-Methyl-2-piperidin-1-yl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]ethanamine,N-(3-Methoxypropyl)-N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2yloxy)phenoxy]ethyl}cyclopropanamine,ethylN-benzyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]glycinate,N-Benzyl-N-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]glycine,N-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-beta-alanine,2-{4-[(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl]phenoxy}[1,3]thiazolo[4,5-b]pyridine,5-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,meso-1-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}urea,6-Chloro-2-(4-piperidin-1-ylmethyl-phenoxy)[1,3]thiazolo[4,5-b]pyridine,1-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-carboxamide,1-{4-[(6-Fluoro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-carboxamide,1-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}piperidine-4-carboxamide,meso-endo-N-[8-{4-[(6-Chloro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,meso-endo-N-[8-{4-[(6-Fluoro[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,meso-endo-N-[8-{4-[(7-Methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)oxy]benzyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.2]oct-2-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyridine,meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-b]pyridin-2-ylmethyl)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)[1,3]thiazolo[4,5-b]pyridine,meso-N-[(3-endo)-8-{2-[4-([,3]Thiazolo[4,5-b]pyridin-2-ylmethyl)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}benzyl)[1,3]thiazolo[4,5-b]pyridine,2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[4,5-c]pyridine,meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,N-(2-Hydroxy-1,1-dimethylethyl)-1-(2-{[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]oxy}ethyl)piperidine-4-carboxamide,2-{[4-({2-[4-(Trifluoromethyl)piperidin-1-yl]ethyl}oxy)phenyl]oxy}[1,3]thiazolo[4,5-c]pyridine,N-(Cyclopropylmethyl)-N-{[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]methyl}propan-1-amine,2-({4-[(4-Pyridin-4-ylpiperidin-1-yl)methyl]phenyl}oxy)[1,3]thiazolo[4,5-c]pyridine,N-{1-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-yl)cyclopropanecarboxamide,(4-Chlorophenyl)(1-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-yl)methanone,N-Propyl-N-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenyl]ethyl}propan-1-amine,meso-3-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)benzyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide,2-[4-(2-Pyrrolidin-1-ylethyl)phenoxy][1,3]thiazolo[4,5-c]pyridine,1-Methyl-4-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]piperazin-2-one,meso-(3-exo)-8-Acetyl-N-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]octan-3-amine,meso-8-{2-[4-([1,3]Thiazolo[4,5-c]pyridin-2-yloxy)phenoxy]ethyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxamide,N-(Cyclopropylmethyl)-N-{2-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)phenoxy]ethyl}-beta-alanine,meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethoxy}phenoxy)[1,3]thiazolo[4,5-c]pyridine,N-Ethyl-N-[4-([1,3]thiazolo[4,5-c]pyridin-2-yloxy)benzyl]cyclohexanamine,2-[4-(Piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[5,4-c]pyridine,meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,1-(1-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-yl)pyrrolidin-2-one,2-(4-{2-[(1R,4R)-5-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy)[1,3]thiazolo[5,4-c]pyridine,3-[(Cyclopropylmethyl){2-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}amino]propan-1-ol,N-Methyl-N-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)benzyl]cyclohexanamine,2-{4-[2-(4-Acetylpiperazin-1-yl)ethyl]phenoxy}[1,3]thiazolo[5,4-c]pyridine,meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}urea,N-(Cyclopropylmethyl)-N-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)benzyl]propane-1,3-diamine,3-(Cyclopropyl{2-[4-([1,3]thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}amino)propan-1-ol,2-(4-{[4-(Pyridin-2-ylcarbonyl)piperazin-1-yl]methyl}phenoxy)[1,3]thiazolo[5,4-c]pyridine,2-{4-[(4-Acetyl-1,4-diazepan-1-yl)methyl]phenoxy}[1,3]thiazolo[5,4-c]pyridine,2-[4-({4-[(4-Methylpiperazin-1-yl)carbonyl]piperidin-1-yl}methyl)phenoxy][1,3]thiazolo[5,4-c]pyridine,2-[4-(2-Azetidin-1-ylethoxy)phenoxy][1,3]thiazolo[5,4-c]pyridine,5-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,2-(4-{[4-(Pyridin-3-yloxy)piperidin-1-yl]methyl}phenoxy)[1,3]thiazolo[5,4-c]pyridine,meso-N-{(3-exo)-8-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}methanesulfonamide,N-[(1-{2-[4-([1,3]Thiazolo[5,4-c]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-yl)methyl]acetamide,2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethoxy}phenoxy)[1,3]thiazolo[5,4-b]pyridine, (1S,4S)-5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,1-{2-[4-([1,3]Thiazoolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxamide,1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol,2-{4-[2-(4-Pyridin-2-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[5,4-b]pyridine,4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,4-Phenyl-1-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,2-(4-{2-[4-(2-Methoxyphenyl)piperidin-1-yl]ethoxy}phenoxy)[1,3]thiazolo[5,4-b]pyridine,2-{4-[2-(4-Pyridin-4-ylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[5,4-b]pyridine,1-(1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidin-4-yl)pyrrolidin-2-one,1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxylicacid,2-(4-{2-[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)[1,3]thiazolo[5,4-b]pyridine,meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,meso-2-(4-{2-[3-Acetyl-3,8-diazabicyclo[3.2.1]oct-8-yl]ethyl}phenoxy)[,3]thiazolo[5,4-b]pyridine,1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}piperidine-4-carboxamide,1-(1-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}piperidin-4-yl)pyrrolidin-2-one,2-{4-[2-(5-Acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl]phenoxy}[1,3]thiazolo[5,4-b]pyridine,5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide,meso-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxamide,meso-1-[(3-endo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]urea,(1S,4S)-5-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,1-{1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrolidin-2-one,1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-5-methyl[1,3]thiazolo[5,4-b]pyridine,meso-N-{(3-endo)-8-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)-6-fluoro[1,3]thiazolo[5,4-b]pyridine,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[1,3]thiazolo[5,4-b]pyridine,1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylicacid,2-{4-[2-(4-Methyl-1,4-diazepan-1-yl)ethoxy]phenoxy}[1,3]thiazolo[5,4-b]pyridine,meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,2-[(Cyclopropylmethyl){2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}amino]ethanol,7-Methyl-2-({4-[(4-pyridin-4-ylpiperazin-1-yl)methyl]phenyl}oxy)[1,3]thiazolo[4,5-b]pyridine,meso-(3-endo)-8-Acetyl-N-{[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl}-8-azabicyclo[3.2.1]octan-3-amine,meso-(3-exo)-8-Acetyl-N-{[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methyl}-8-azabicyclo[3.2.1]octan-3-amine,N-Ethyl-N-{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}cyclopropanamine,meso-N-[(3-exo)-8-{2-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)phenyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]methanesulfonamide,meso-(3-exo)-3-{[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxamide,4-Methyl-1-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)benzyl]-1,4-diazepan-5-one,N-{1-[4-([1,3]Thiazolo[5,4-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}propenamide,2-(4-{2-[4-(Cyclopropylcarbonyl)-1,4-diazepan-1-yl]ethyl}phenoxy)[1,3]thiazolo[5,4-b]pyridine,meso-N-Methyl-N-{(3-exo)-8-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}acetamide,2-(Cyclopropyl{2-[4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenoxy]ethyl}amino)ethanol,2-{4-[(4-Pyridin-2-ylpiperazin-1-yl)methyl]phenoxy}[1,3]thiazolo[5,4-b]pyridine,2-(4-{2-[(1R,4R)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)[1,3]thiazolo[5,4-b]pyridine,7-Methyl-2-[4-(piperidin-1-ylmethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl}phenoxy)-7-methyl[1,3]thiazolo[5,4-b]pyridine,1-{4-[(7-Methyl[1,3]thiazolo[5,4-b]pyridin-2-yl)oxy]benzyl}piperidine-4-carboxamide,4-Phenyl-1-{2-[4-([1,3]thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,2-{4-[2-(4-Benzylpiperidin-1-yl(ethoxy]phenoxy}[1,3]thiazolo[4,5-b]pyrazine,1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol,4-(4-Chlorophenyl)-1-{2-[4-([1,3]thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}piperidin-4-ol,1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}piperidine-4-carboxamide,2-(4-{[(1S,4S)-5-Acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenoxy)[1,3]thiazolo[4,5-b]pyrazine,meso-N-[(3-endo)-8-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenoxy]ethyl}-8-azabicyclo[3.2.1]oct-3-yl]acetamide,2-[4-(2-Morpholin-4-ylethoxy)phenoxy][1,3]thiazolo[4,5-b]pyrazine,2-({4-[(4-Pyrimidin-2-ylpiperazin-1-yl)methyl]phenyl}oxy)[1,3]thiazolo[4,5-b]pyrazine,2-[(4-{[4-(2-Thienylacetyl)piperazin-1-yl]methyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyrazine,1-{2-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)phenyl]ethyl}-1,4-diazepan-5-one,2-{[4-(2-Azepan-1-ylethyl)phenyl]oxy}[1,3]thiazolo[4,5-b]pyrazine,2-({4-[2-(4-Fluoropiperidin-1-yl)ethyl]phenyl}oxy)[1,3]thiazolo[4,5-b]pyrazine,2-[(4-{[4-(Pyrimidin-2-yloxy)piperidin-1-yl]methyl}phenyl)oxy][1,3]thiazolo[4,5-b]pyrazine,meso-1-{(3-exo)-8-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)benzyl]-8-azabicyclo[3.2.1]oct-3-yl}urea,2-(4-{2-[4-(Pyridin-2-yloxy)piperidin-1-yl]ethyl}phenoxy)[1,3]thiazolo[4,5-b]pyrazine,3-Acetyl-9-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]-3,9-diazaspiro[5.5]undecane,and1-[4-([1,3]Thiazolo[4,5-b]pyrazin-2-yloxy)benzyl]piperidine-4-carboxamide,and pharmaceutically acceptable salts, prodrugs, and solvates thereof ofany of the foregoing compounds.

In certain embodiments, the compound of formula (IV) is the compoundknown as JNJ-40929837, which has the following structure:

JNJ40929837 analogs and derivatives useful in the methods of theinvention include the LTA4H inhibitor compounds described in U.S. Pat.Nos. 7,939,527; and 8,357,684, which are incorporated herein byreference.

In certain embodiments, the LTA4H modulatory agent is adiazabicyclo[2.2.1]heptane derivative. In some embodiments, the LTA4Hmodulatory agent is described by the formula (V):

where:

r is 0 to 4;

R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are each independentlyselected from hydrogen, —R^(13a)—OR^(10a), —R^(13a)—C(═O)OR^(10a),—R^(13a)—C(═O)R^(10a), alkyl, halo, haloalkyl, cyano, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,optionally substituted heterocyclyl, and optionally substitutedheterocyclylalkyl;

R¹⁶ is a direct bond, —O—, —R^(12a)—O—, —O—R^(12a)—, —O—R^(12a)—O—, anoptionally substituted straight or branched alkylene chain, anoptionally substituted straight or branched alkenylene chain, or anoptionally substituted straight or branched alkynylene chain;

R¹⁴ is a direct bond, —O—R^(12b)—, an optionally substituted straight orbranched alkylene chain, an optionally substituted straight or branchedalkenylene chain, or an optionally substituted straight or branchedalkynylene chain;

R¹³ is hydrogen, alkyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—R^(13a)—OR^(10a), —R¹³—O—R^(14a)—C(═O)OR^(10a), —R^(13a)—C(═O)R^(10a),—R^(13a)—C(═O)OR^(10a), —R^(13a)—C(═O)—R^(14a)—C(═O)OR^(10a),—R^(13a)—C(═O)—R^(13a)—N(R^(10a))R^(11a),—R^(13a)—C(═O)—R^(14a)—S(═O)_(t)N(R^(10a))R^(11a) (where t is 1 or 2),or —R^(14a)—S(═O)_(p)R^(10a) (where p is 0, 1 or 2);

or R¹³ is aralkyl optionally substituted with one or more substituentsselected from the group consisting of halo, nitro, cyano, optionallysubstituted heteroaryl, hydroxyiminoalkyl, —R^(13a)—OR^(10a),—R^(13a)—C(═O)R^(10a), —R^(13a)—C(═O)OR^(10a),—R^(13a)—C(═O)—R^(13a)—N(R^(10a))R^(11a),—R^(13a)—C(═O)N(R^(10a))—R^(14a)—N(R^(10a))R^(11a),—R^(13a)—S(═O)_(t)N(R^(10a))R^(11a), —R^(13a)—N(R^(10a))R^(11a)—,—R^(13a)—N(R^(10a))C(═O)R^(10a),—R^(13a)—N(R^(10a))C(═O)—R^(13a)—N(R^(10a))R^(11a),—R^(13a)—N(R^(10a))—R^(13a)—C(═O)OR^(10a),—R^(13a)—N(R^(10a))C(═O)—R^(14a)—S(═O)_(t)N(R^(10a))R^(11a),—R^(13a)—N(R^(10a))C(═O)—R^(13a)—N(R^(10a))C(═O)R^(10a),—R^(13a)—N(R^(10a))C(═O)—R^(13a)—N(R^(10a))—R^(14a)—N(R^(10a))R^(11a),—R^(13a)—N(R^(10a))S(═O)_(t)N(R^(10a))R^(11a), and—R^(13a)—O—R^(14a)—C(═O)OR^(10a), where t is 1 or 2;

each R¹⁵ is independently selected from —O—R^(10a), alkyl, hydroxyalkyl,halo, haloalkyl, aryl or aralkyl;

each R^(10a) and R^(11a) is independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, or optionallysubstituted heterocyclylalkyl;

or R^(10a) and R^(11a), together with the nitrogen to which they areattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl;

each R^(12a) is an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chain,or an optionally substituted straight or branched alkynylene chain;

R^(12b) is an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chain,or an optionally substituted straight or branched alkynylene chain;

each R^(13a) is a direct bond, an optionally substituted straight orbranched alkylene chain, an optionally substituted straight or branchedalkenylene chain, or an optionally substituted straight or branchedalkynylene chain;

and each R^(14a) is an optionally substituted straight or branchedalkylene chain, an optionally substituted straight or branchedalkenylene chain, or an optionally substituted straight or branchedalkynylene chain.

In certain embodiments of formula (V), the compound is selected from4-[[(1S,4S)-5-[(4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[(4-fluorophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]-benzoicacid,4-[[(1S,4S)-5-[(4-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[3-(4-phenoxyphenyl)propyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-(4-chlorophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[2-(4-phenoxyphenyl)ethyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-(2-phenoxyethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-(4-bromophenoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[(2′-fluoro[1,1′-biphenyl]-4-yl)oxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[4-(3-furanyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[4-(trifluoromethyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-]4-acetylphenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[4-(3-thienyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[4-(3,5-dimethyl-4-isoxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[(3-fluoro-4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[3-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2]yl]methyl]benzoicacid,4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, 4-[[(1S,4S)-5-[(4-fluoro-2-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[(3-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[(2-fluoro-4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[(2,4-diphenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-([1,1′-biphenyl]-4-ylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid,4-[[(1S,4S)-5-[(4-phenoxyphenyl)methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid,4-[[(1S,4S)-5-[[4-(2-phenoxyethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid,4-[[(1S,4S)-5-[[4-(2-phenylethoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzeneaceticacid, methyl 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate,4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, and methyl4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.

In some embodiments of formula (V), the compound is selected from4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, and methyl 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.

In some embodiments of formula (V), the compound is selected from4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoicacid, and methyl 4-[[(1S,4S)-5-[[4-[4-(2-thiazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate.

In certain embodiments, the compound of formula (V) is the compoundknown as Acebilustat (CTX-4430), which has the following structure:

Acebilustat analogs and derivatives useful in the methods of theinvention include the compounds described in U.S. Pat. No. 7,737,145;and U.S. Patent Application Publication No. 20100210630A1, the contentsof each of which are incorporated by reference herein. LTA4H inhibitorcompounds also include those described in U.S. Pat. Nos. 9,822,106;9,856,249; and 9,777,006, the contents of each of which are incorporatedby reference herein.

In some embodiments the LTA4H modulatory agent is a heterocycliccompound described by the formula (VI):

where:

Ar is selected from aryl, heteroaryl, aryl substituted with from one tothree substituents independently selected from the group consisting ofhalogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,fluoroloweralkoxy, hydroxy, hydroxy(C₁-C₄) alkyl, formyl,formyl(C₁-C₄)alkyl, cyano, cyano(C₁-C₄)alkyl, benzyl, benzyloxy, phenyl,substituted phenyl, heteroaryl, heterocyclylalkyl, substitutedheteroaryl, and nitro, and heteroaryl substituted with from one to threesubstituents independently selected from the group consisting ofhalogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl, heteroaryl,heterocyclylalkyl and nitro;

X is selected from direct bond, O, SO, S(O₂), NR^(1f), CH₂, CF₂, CH₂CH₂,CH₂NR^(1f), NR^(1f)CH₂, CH═CH, C═O, CH₂C═O, CR^(1aa)R^(1bb),OCR^(1aa)R^(1bb)CR^(1aa)R^(1bb)O; SO₂NR^(1f), NR^(1f)SO₂, C(═O)NR^(1f)and NR^(1f)C(═O);

R^(1f) is selected separately in each occurrence from H and lower alkyl;

R^(1aa) is selected from H, OH and lower alkyl;

R^(1bb) is selected from H and lower alkyl, or R^(1aa) and R^(1bb) takentogether may form a 3-6 membered ring, which may optionally contain aheteroatom chosen from O, S, and N;

HetAr is an aryl or heteroaryl ring attached via a ring carbon to Q,further characterized in that Q and X cannot be on adjacent positions insaid aryl or heteroaryl ring;

Q is chosen from —O—, —NR^(1f)— and S(O)_(p);

Q and X cannot be on adjacent positions in said benzene or pyridinering;

p is zero, 1 or 2;

n is an integer selected from 1-5;

HET is selected from 4-7-membered saturated nitrogenous heterocycle, and4-7-membered saturated nitrogenous heterocycle substituted with one ortwo substituents independently selected from halogen, hydroxyl, amino,carboxy, loweralkyl, loweracyl, loweralkoxy, N-oxide, fluoroloweralkyl,fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl, heteroaryland nitro; and

taken together ZW is H or Z is (CH₂)₁₋₁₀, in which one or two (CH₂) mayoptionally be replaced by —O—, —NR^(1f)—, —SO—, —S(O)₂—, —C(═O)— or—CO(NH)—, provided that said —O—, —NR^(1f)—, —SO—, —S(O)₂—, —C(═O)— or—C═O(NH)— are not at the point of attachment to HET and are separated byat least one —(CH₂)—;

W is selected from acyl, hydroxyl, carboxyl, amino, —C(O)NHR^(4a),aminoacyl, —COOalkyl, —CHO, heterocyclyl, substituted aryl, substitutedheterocyclyl, sulfonamide, —C(O)fluoroalkyl, —C(O)CH₂C(O)Oalkyl,—C(O)CH₂C(O)Ofluoroalkyl, —SH, —C(O)NH(OH), —C(O)N(OH)R^(4a),—N(OH)C(O)OH, —N(OH)C(O)R^(4a); and

R^(4a) is selected from H, (C₁-C₄) alkyl and phenyl(C₁-C₄) alkyl.

In some embodiments of formula (VI), the compound is described byformula (VIa):

Where:

X is selected from the group consisting of direct bond, O, SO, S(O₂),NR¹, CH₂, CF₂, CH₂O, C═O and CH₂C═O;

R¹⁷ is chosen from halogen, CF₃, methyl, methoxy, CF₃O;

n is 1 or 2;

Z is (CH₂)₁₋₁₀, in which one or two (CH₂) may optionally be replaced by—O—, —NR^(1f)—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—, provided that said—O—, —NR^(1f)—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)— are not at the pointof attachment to HET and are separated by at least one —(CH₂)—;

W is selected from acyl, hydroxyl, carboxyl, amino, —C(O)NHR^(4a),aminoacyl, —COOalkyl, —CHO, heterocyclyl, substituted aryl, substitutedheterocyclyl, sulfonamide, —C(O)fluoroalkyl, —C(O)CH₂C(O)Oalkyl,—C(O)CH₂C(O)Ofluoroalkyl, —SH, —C(O)NH(OH), —C(O)N(OH)R^(4a),—N(OH)C(O)OH, —N(OH)C(O)R^(4a); and

R^(4a) is selected from H, (C₁-C₄) alkyl and phenyl(C₁-C₄) alkyl.

In certain embodiments of formula (VIa), X is O or CH₂, n is 1 or 2, Zis C₁₋₄ alkylene and W is COOH.

In certain embodiments, the compound of formula (VI) or (VIa) is thecompound known as DG-051, which has the following structure:

DG051 analogs and derivatives useful in the methods of the inventioninclude the LTA4H inhibitor compounds described in U.S. Pat. No.7,402,684; and Sandanayaka et al. J Med. Chem. 2010 Jan. 28;53(2):573-85; Bio-org Med Chem. Lett. 2009 Nov. 15; 19(22):6275-9, eachof which is incorporated herein by reference.

In some embodiments the LTA4H modulatory agent is described by theformula (VII):

Ar¹-Q¹-AR²—Y¹—R¹⁸—Z¹  (VII)

where:

Ar¹ is an aryl moiety selected from phenyl, mono-, di-, ortri-substituted phenyl with the substituents selected from the Cl, Br,F, CF₃, lower alkyl, lower alkoxy, NH₂, NO₂ and OH; Ar² is

wherein R¹⁹ is selected from H, halogen, lower alkyl, lower alkoxy,nitro or hydroxy, R²⁰ and R²¹ are each independently selected from H,halogen, lower alkyl, lower alkoxy, amino, nitro or hydroxy;

Q¹ is —O—, or —CH₂—, —OCH₂—, —CH₂O—, —NH—, —NHCH₂—, —CH₂NH—, —CF₂—,—CH═CH—, —CH₂—CH₂—, and a carbon-carbon single bond;

Y¹ is selected from —O—, —S—, —NH—, —S(O)—, and —S(O₂)—;

R¹⁸ is selected from linear or branched C₂-C₆ alkylenyl, orC(R²²)(R²³)—(CH₂)m, wherein R²² and R²³ are each independently selectedfrom H and lower alkyl, and m is 1, 2 or 2; and

Z is

wherein at least one of R²⁴ and R²⁵ is —(CH₂)_(a)COR²⁶ and the other isselected from H, lower alkyl, allyl, benzyl, —(CH₂)_(a)COR²⁶, and—(CH₂)_(a)—OH;

R²⁶ is —OR²⁷, where R²⁷ is H, lower alkyl or benzyl; and

a is an integer from 0 to 5, provided that when R²⁴ and R²⁵ are both—(CH₂)_(a)COR²⁶, then a is not 0.

In certain embodiments of formula (VII), Ar¹-Q¹-AR²—Y¹ is:

-   -   Where:    -   Q is —O— or —CH₂—;    -   R²⁰ and R²⁸ are each independently selected from H, lower alkyl,        lower alkoxy, halogen, amino and nitro.

In certain embodiments of formula (VII), the compound is selected from3-[[3-[4(phenylmethyl)phenoxy]propyl]amino]propanoic acid,3-[methyl[3-[4(phenylmethyl)phenoxy]propyl]amino]propanoic acid,3-[[4-[4(phenylmethyl)phenoxy]butyl]amino]propanoic acid,3-[[3-(4-phenoxyphenoxy)propyl]amino]propanoic acid,3-[methyl[3-(4-phenoxyphenoxy)propyl]amino]propanoic acid,3-[[4-(4-phenoxyphenoxy)butyl]amino]propanoic acid; and3-[[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoicacid, monohydrochloride. In certain embodiments of formula (VII), thecompound is selected from ethyl3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, phenylmethyl 3[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, ethyl3-[[3-(4-phenoxyphenoxy)propyl]-amino]propanoate, ethyl3-[[methyl-[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, methyl3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, hydrate,ethyl 3-[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoate, phenylmethyl3-[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoate, phenylmethyl3-[[3-(4-phenoxyphenoxy)propyl]amino]propanoate, phenylmethyl3-[methyl[3-(4-phenoxyphenoxy)propyl]amino]propanoate, phenylmethyl3-[[4-(4-phenoxyphenoxy)butyl]amino]propanoate, methyl3-[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoate,ethyl 3-[[4-[4-phenoxyphenoxy]butyl]amino]propanoate, and methyl3-[[3-[4-(4-fluorophenoxy)phenoxy]propyl]methylamino]propanoate.

In certain embodiments, the compound of formula (VII) is the compoundknown as SC-57461A, which has the following structure:

SC-57461A analogs and derivatives useful in the methods of the inventioninclude the LTA4H inhibitor compounds described in U.S. Pat. Nos.5,723,492; 6,162,823; 5,585,492; and 5,719,306, each of which isincorporated herein by reference.

In certain embodiments, the LTA4H modulatory agent is of the formula(VIII):

where:

Y² is selected from N, or CR³², wherein R³² is selected from hydrogen,alkyl or substituted alkyl;

Y³ is selected from S, O, NR³³, wherein R³³ is selected from H, alkyl orsubstituted alkyl;

each R²⁹ and R³⁰ are independently selected from halogen, lower alkyl,lower alkoxy, amino, nitro, and hydroxy;

R³¹ is selected from H, halogen, lower alkyl, lower alkoxy, amino,nitro, and hydroxy;

n is an integer from 0 to 5; and

m is an integer from 0 to 4.

In some embodiments the compound of formula (VIII) is4-(4-benzylphenyl)thiazol-2-amine (ARM1), or an analog thereof. ARM1 hasthe following structure:

In certain embodiments, ARM1 is in the form of a salt (e.g., a hydrogenbromide salt or a hydrogen chloride salt).

In some embodiments, the LTA4H modulatory agent is a proline derivative.In some embodiments, the LTA4H modulatory agent is described by theformula (IX):

where:

R³⁴ is hydroxy or lower alkoxy;

R³⁵ is hydrogen or lower alkyl;

R³⁶ is hydrogen or lower alkanoyl; and

n is 0, 1 or 2, or pharmaceutically acceptable salts thereof, whereinsaid lower alkoxy, lower alkyl and lower alkanoyl groups having up to 7carbon atoms.

In certain embodiments of a compound of formula (IX), R³⁴ is hydroxy. Incertain cases, R³⁴ is hydroxy, R³⁵ is methyl and R³⁶ is H. In certaincases, the compound of formula (IX) is a proline derivative in theL-form.

In some embodiments the compound of formula (IX) is captopril, or ananalog thereof. The structure of captopril is as follows:

Captopril analogs and derivatives useful in the methods of the inventioninclude the compounds described in U.S. Pat. Nos. 4,046,889, and4,105,776, each of which is incorporated herein by reference.

In some embodiments, the LTA4H modulatory agent is a resveratrolderivative. In some embodiments, the LTA4H modulatory agent is describedby the formula (X):

where:

R³⁷, R³⁸ and R³⁹ are each independently —OR⁴⁰, wherein each R⁴⁰ isindependently selected from hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy.

In some embodiments compound of formula (X) is pinostilbene hydrate, oran analog thereof. The structure of pinostilbene hydrate is as follows:

Pinostilbene hydrate analogs useful in the methods of the inventioninclude the LTA4H inhibitor compounds described in Low et al. ScientificReports, (2017) 7:44449, which is incorporated herein by reference.

In some embodiments, the LTA4H modulatory agent is an arylpyrazole, or apharmaceutically acceptable salt thereof. In certain embodiments, theLTA4H modulatory agent is of the formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

A¹ and A² are each independently selected from the group consisting ofCH and N;

L¹ is a linker selected from the group consisting of —O— and —CH₂—;

B is a 9- or 10-membered ring selected from:

wherein each B ring may optionally be further substituted by—(C₁-C₆)alkyl;

L² is absent or a —(CH₂)_(n)— linker, wherein n is an integer selectedfrom 1, 2 and 3, and wherein one —(CH₂)— moiety of said L² linker mayoptionally be replaced, where possible, by —O— and wherein each —(CH₂)—of said L² linker may be substituted with one to two groups selectedfrom the group consisting of —OH, -halo, ═O, —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, -(4-to 7-membered)heterocyclyl, and phenyl; whereintwo —(C₁-C₆)alkyls groups, when attached to the same carbon atom of saidL² linker moiety may join to form a —(C₃-C₆)cycloalkyl;

R¹ is selected from:

(a) a group of formula —N(R²)(R³), wherein R² and R³ are eachindependently selected from the group consisting of —H, —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, and -(4-to 7-membered)heterocyclyl, wherein each ofsaid —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, and -(4-to7-membered)heterocyclyl of said R² and R³ may optionally beindependently substituted by 1 to 3 R⁴ groups;

R⁴ is selected from the group consisting of halo, —OH, ═O,—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, N(R⁵)₂, —C(O)—R⁵, —N(R⁵)—C(O)—R⁵,—C(O)—N(R)₂, —(C₃-C₆)cycloalkyl optionally substituted by—C(O)—(C₁-C₆)alkyl, -(4-to 7-membered)heterocyclyl optionallysubstituted by —C(O)—(C₁-C₆)alkyl, and phenyl; and

each R⁵ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, and -(4-to 7-membered)heterocyclyl;

(b) a 4-to 9-membered N-heterocyclic ring, wherein said 4-to 9-memberedN-heterocyclic ring is optionally independently substituted with one ormore substituents selected from the group consisting of (i) 1 G¹ groupor (ii) 1 to 3 G² groups; wherein

G¹ is selected from the group consisting of -L⁴-(C₁-C₆)alkyl,-L⁴-(C₃-C₆)cycloalkyl, -L⁴-(C₃-C₆)heterocyclyl, and -L⁴-phenyl; whereineach of said —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, -(4-to7-membered)heterocyclyl, and phenyl substituents may optionally beindividually substituted by 1 to 4 R⁶ groups;

L⁴ is absent or selected from the group consisting of —O—, —C(O)—,—N(R⁷)—, —C(O)—N(R⁷)—, —N(R⁷)—C(O)—, and —N(R⁷)—S(O)—;

—R⁶ is selected from the group consisting of halo, —OH, ═O, —CN,—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —N(R⁷)₂, —C(O)—R⁷, —C(O)—O—R⁷,—N(R⁷)—C(O)—R⁷, —C(O)—N(R⁷)₂, —S(O)_(j)—R⁷, —(C₃-C₆)cycloalkyl, -(4-to7-membered)heterocyclyl, and phenyl optionally substituted with—C(O)—O—R⁷;

each R⁷ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, and -(4-to 7-membered)heterocyclyl;and

G² is independently selected from the group consisting of -halo, —OH,═O, —CN, —O(C₁-C₆)alkyl and —(C₁-C₆)alkyl optionally substituted with—O(C₁-C₆)alkyl; or

(c) a group selected from the group consisting of atetrahydro-2H-pyranyl, —C(O)—OH and OH, wherein j is an integer selectedfrom 0, 1 and 2.

In some embodiments, the LTA4H modulatory agent is a compound selectedfrom2-Methoxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperazin-1-yl)-ethanone,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperazin-1-yl)-ethanone,5-(2H-Pyrazol-3-yl)-2-(6-pyrrolidin-1-ylmethyl-naphthalen-2-yloxy)-pyridine,1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperidin-4-ol,1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperidine-4-carboxylicacid amide,N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperidin-4-yl)-acetamide,(S)-3-Hydroxy-1-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-naphthalen-2-ylmethyl}-piperidin-4-yl)-pyrrolidin-2-one,Dimethyl-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-chroman-2-ylmethyl}-amine,1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-chroman-2-ylmethyl}-piperidine-4-carboxylicacid amide,2-Hydroxy-1-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,3-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-oxazolidin-2-one,1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-propan-1-one,(S)-2-Hydroxy-1-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-propan-1-one,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-pyrazolo[1,5-a]pyridine,(1-Hydroxy-cyclopropyl)-(4-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-methanone,(S)-7-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexahydro-oxazolo[3,4-a]pyrazin-3-one,2-(2,2-Dioxo-2-λ-6-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexahydro-pyrrolo[1,2-a]pyrazin-6-one,6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2-pyrrolidin-1-ylmethyl-quinoline,2-(2-Oxa-6-aza-spiro[3.4]oct-6-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,2-Azetidin-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,2-Azepan-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,2-Piperidin-1-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,1-(8-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone,Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amine,2-Methyl-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-propan-1-one,2-Hydroxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,2-Methoxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-propan-1-one,8-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-1,8-diaza-spiro[4.5]decan-2-one,3-Oxo-3-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-propionitrile,1-(5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-ethanone,2-Hydroxy-N-methyl-N-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetamide,(R)-2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-propionamide,(1a,5a,6a)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid amide,1-{3-[(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-methyl]-azetidin-1-yl}-ethanone,N-Methyl-N-(1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetamide,2-Hydroxy-1-((R)-3-methyl-4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,2-Methanesulfonyl-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,(1a,5a,6a)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid (2-hydroxy-2-methyl-propyl)-amide,N-((1a,5a,6a)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-acetamide,1-((S)-3-Hydroxymethyl-4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazine-1-carboxylicacid amide,2-Hydroxy-1-(3-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethanone,2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-1-pyrrolidin-1-yl-ethanone,2-Hydroxy-N-(4-methyl-1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetamide,2-(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-acetamide,2-(2-Oxa-6-aza-spiro[3.5]non-6-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,(S)-3-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-pyrrolidin-2-one,2-Hydroxy-1-(8-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-1,8-diaza-spiro[4.5]dec-1-yl)-ethanone,(S)-2-Phenyl-2-({6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-acetamide,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-1H-benzoimidazole,2-((2R,6S)-2,6-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,6-[4-(2H-Pyrazol-3-yl)-benzyl]-2-pyrrolidin-1-ylmethyl-1H-benzoimidazole,2-((3S,5S)-3,5-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-((2S,6S)-2,6-Dimethyl-morpholin-4-ylmethyl)-6-[4-(2H-pyrazol-3-yl)-benzyl]-1H-benzoimidazole,2,2,2-Trifluoro-1-(4-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperazin-1-yl)-ethanone,(1S,5S)-3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-8-oxa-3-aza-bicyclo[3.2.1]octane,2-(1-Morpholin-4-yl-cyclopropyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-benzyl]-1H-benzoimidazole,2-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-((S)-3-Methyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-1H-benzoimidazole,2-(4-Isopropyl-piperazin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-ylmethyl]-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,(S)-1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-pyrrolidin-3-ol,5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-yl}-piperidin-2-one,(S)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-yloxy}-piperidin-2-one,5-[4-(1H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazole-2-carboxylic acid,2,2-Dimethyl-1-(4-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperazin-1-yl)-propan-1-one,2,2,2-Trifluoro-1-(1-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperidin-4-yl)-ethanol,2-(2-Oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyridin-3-ylmethyl-1H-benzoimidazole,((S)-sec-Butyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(S)-1-(tetrahydro-furan-2-yl)methyl]-amine,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(S)-tetrahydro-furan-3-yl-amine,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(R)-tetrahydro-furan-3-yl-amine,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1-(3-pyrrolidin-1-yl-propyl)-1H-indazole,((R)-sec-Butyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(R)-1-(tetrahydro-furan-2-yl)methyl]-amine,((S)-2-Methoxy-1-methyl-ethyl)-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole,2-(3-Morpholin-4-yl-propyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-2H-indazole,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-furan-2-ylmethyl)-amine,Ethyl-((S)-2-methoxy-1-methyl-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,[1,4]Dioxan-2-ylmethyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,N-[1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperidin-4-yl]-acetamide,2-((S)-1-Methyl-pyrrolidin-2-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,1-[4-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperazin-1-yl]-ethanone,(2-Methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-pyran-3-ylmethyl)-amine,1-[4-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-piperazin-1-yl]-ethanone,1-[4-(2-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indazol-1-yl}-ethyl)-piperazin-1-yl]-ethanone,1-[4-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-propyl)-piperazin-1-yl]-ethanone,(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetonitrile,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-furan-2-ylmethyl)-amine,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-thiomorpholin-4-ylmethyl-1H-benzoimidazole,1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidine-4-carbonitrile,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(S)-1-(tetrahydro-furan-2-yl)methyl]-amine,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-[(R)-1-(tetrahydro-furan-2-yl)methyl]-amine,1-(2-Morpholin-4-yl-ethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-indazole,N—((S)-sec-Butyl)-N-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-acetamide,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-furan-3-ylmethyl)-amine,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(3-pyrrolidin-1-yl-propyl)-2H-indazole,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-pyran-4-ylmethyl)-amine,(R)-1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pyrrolidine-3-carbonitrile,1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-yl}-ethyl)-piperazin-1-yl]-ethanone,N-[1-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-propyl)-piperidin-4-yl]-acetamide,1-[4-(Methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-piperidin-1-yl]-ethanone,1-(2-Morpholin-4-yl-ethyl)-5-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-1H-indazole,2-Hydroxy-2-methyl-N-[1-(2-{5-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-indazol-2-yl}-ethyl)-piperidin-4-yl]-propionamide,3-Morpholin-4-ylmethyl-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-1H-indazole,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-benzooxazole,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-yl}-piperazin-1-yl)-ethanone,N-[1-(3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-propyl)-piperidin-4-yl]-acetamide,(S)-5-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indazol-1-ylmethyl}-pyrrolidin-2-one,3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-propan-1-ol,(S)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-isoquinolin-1-yloxymethyl}-pyrrolidin-2-one,2-(2-Morpholin-4-yl-ethoxy)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,N-[2-({6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amino)-ethyl]-acetamide,(2-Methoxy-ethyl)-methyl-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-amine,Dimethyl-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-amine,4-(1-{1-[4-(2H-Pyrazol-3-yl)-benzyl]-1H-indol-5-ylmethyl}-piperidin-4-yl)-benzoicacid,N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-acetamide,5-(2H-Pyrazol-3-yl)-2-(2-pyrrolidin-1-ylmethyl-2,3-dihydro-benzofuran-6-yloxy)-pyridine,5-(2H-Pyrazol-3-yl)-2-(2-pyrrolidin-1-ylmethyl-benzofuran-6-yloxy)-pyridine,N-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-ylmethyl)-acetamide,1-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-pyrrolidin-2-one,3-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-piperidin-4-yl]-oxazolidin-2-one,N-((endo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,2-Hydroxy-1-(8-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone,N-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-piperidin-4-yl]-acetamide,1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-[1,4]diazepan-1-yl]-ethanone,1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-3-yl}-ethyl)-[1,4]diazepan-1-yl]-ethanone,1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-piperazin-1-yl]-ethanone,1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidine-4-carboxylicacid methylamide,1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-piperidine-4-carboxylicacid methylamide,2-Hydroxy-1-((1S,4S)-5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,2-Hydroxy-1-(4-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-[1,4]diazepan-1-yl)-ethanone,N-[1-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-yl}-ethyl)-piperidin-4-yl]-methanesulfonamide,N-((exo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,1-[4-(2-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2,3-dihydro-benzofuran-3-yl}-ethyl)-piperazin-1-yl]-ethanone,1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidine-4-carboxylicacid amide,2-Hydroxy-1-((1R,4R)-5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,2-Hydroxy-1-(5-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.2]oct-2-yl)-ethanone,1-((1R,4R)-5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,1-(5-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.2]oct-2-yl)-ethanone,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-benzofuran-3-ylmethyl}-piperazin-1-yl)-ethanone,4-((1S,4S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzoicacid methyl ester,4-(1-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperidin-4-yl)-benzoicacid methyl ester,Diethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,2-(4-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,Ethyl-methyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-amine,Ethyl-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,2-(3-Methoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-(3-Methoxy-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,Dimethyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-amine,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-pyran-4-ylmethyl)-amine,N—[(R)-1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-pyrrolidin-3-yl]-acetamide,((S)-sec-Butyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,Dimethyl-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-amine,2-Azepan-1-ylmethyl-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,Cyclopentyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,2-((R)-2-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-(3-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-((R)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-(2-Methoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,N,N-Dimethyl-2-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-acetamide,2-Methoxy-N-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-acetamide,2-((S)-2-Methyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-(3-Methoxy-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-((S)-2-Methoxymethyl-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,3-Methyl-1-{6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-azetidin-3-ol,2-[1,4]Oxazepan-4-ylmethyl-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-[2-(1,1-Dioxo-1-λ-6-thiomorpholin-4-yl)-ethyl]-5-[4-(2H-pyrazol-3-yl)-phenoxy]-2H-indazole,1-[1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperidin-4-yl]-pyrrolidin-2-one,2-[(1S,4S)-1-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)methyl]-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,Cyclopropyl-methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,((R)-sec-Butyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-pyran-3-yl)-amine,2-(3,3-Dimethyl-morpholin-4-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,Isopropyl-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,(2-Methoxy-ethyl)-propyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-(tetrahydro-pyran-4-ylmethyl)-amine,Bis-(2-methoxy-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,Morpholin-4-yl-(1-{6-[4-(2H-pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-methanone,Cyclopentyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,((S)-2-Methoxy-1-methyl-ethyl)-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,3-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-[1,3]oxazinan-2-one,Ethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amine,2-(Ethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amino)-ethanol,2-(4-Ethoxymethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(S)-tetrahydro-furan-3-yl-amine,(1-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-piperidin-2-yl)-methanol,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(3-trifluoromethyl-pyrrolidin-1-ylmethyl)-1H-benzoimidazole,1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidine-4-carboxylicacid dimethylamide,1-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-pyrrolidin-2-one,2-(Propyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amino)-ethanol,N—[(R)-1-(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-pyrrolidin-3-yl]-acetamide,2-Methoxy-N-[1-(2-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-indazol-1-yl}-ethyl)-piperidin-4-yl]-acetamide,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(tetrahydro-pyran-4-ylmethyl)-1H-benzoimidazole,3-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-oxazolidin-2-one,1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-ol,2-((R)-3-Methoxy-pyrrolidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,(2-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-yl}-ethyl)-(tetrahydro-pyran-4-ylmethyl)-amine,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(S)-1-pyrrolidin-2-ylmethyl-1H-benzoimidazole,2-((S)-3-Methoxy-pyrrolidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,1′-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-[1,4′]bipiperidinyl-2-one,(S)-1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-pyrrolidin-3-ol,4-(1-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-morpholin-3-one,2-(4-Methoxy-piperidin-1-ylmethyl)-6-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,(1R,5S)-3-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one,{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-[2-(tetrahydro-pyran-4-yl)-ethyl]-amine,6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-2-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-quinoline,1-{1-[4-(2H-Pyrazol-3-yl)-benzyl]-1H-indol-5-ylmethyl}-azetidin-3-ol,5-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole,5-[4-(2-Pyrrolidin-1-ylmethyl-2,3-dihydro-benzofuran-6-yloxy)-phenyl]-1H-pyrazole,N-(1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2,3-dihydro-benzofuran-2-ylmethyl}-piperidin-4-yl)-acetamide,6-[5-(2H-Pyrazol-3-yl)-pyrimidin-2-yloxy]-2-pyrrolidin-1-ylmethyl-quinoline,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1H-indol-2-ylmethyl}-piperazin-1-yl)-ethanone,1-(4-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-1H-indol-2-ylmethyl}-piperazin-1-yl)-ethanone,1-(4-{6-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-isoquinolin-3-ylmethyl}-piperazin-1-yl)-ethanone,1-[4-(2-{5-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-indol-1-yl}-ethyl)-piperazin-1-yl]-ethanone,2-(4-Morpholin-4-ylmethyl-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,2-((S)-3-Methoxy-pyrrolidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,3-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-8-oxa-3-aza-bicyclo[3.2.1]octane,2-(4-Methoxy-piperidin-1-ylmethyl)-5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazole,(1S,2S)-2-(Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amino)-cyclohexanol,Methyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-(tetrahydro-pyran-4-yl)-amine,1-(4-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,2-(2-Morpholin-4-yl-ethoxy)-6-[4-(1H-pyrazol-3-yl)-phenoxy]-benzothiazole,Cyclopropanecarboxylic acidmethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amide,3,3-Dimethyl-1-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-pyrrolidin-2-one,Cyclopropanecarboxylic acidethyl-{5-[4-(2H-pyrazol-3-yl)-phenoxy]-1H-benzoimidazol-2-ylmethyl}-amide,2-Methoxy-N-(1-{6-[5-(1H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetamide,N-(1-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-piperidin-4-yl)-acetamide,N-((endo)-8-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,N-((exo)-8-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,1-((S)-5-{6-[5-(1H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-2-ylmethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone,1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinoxalin-2-ylmethyl}-piperazin-1-yl)-ethanone,2-(1,1-Dioxo-1-λ-6-thiomorpholin-4-ylmethyl)-6-[5-(1H-pyrazol-3-yl)-pyridin-2-yloxy]-quinoline,6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-quinoline,2-Azetidin-1-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,1-(8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone,6-[4-(2H-Pyrazol-3-yl)-phenoxy]-2-pyrrolidin-1-ylmethyl-imidazo[1,2-a]pyridine,1-(4-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-piperazin-1-yl)-ethanone,N-((exo)-8-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-quinolin-2-ylmethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide,3-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridine,(S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-2-ylmethyl}-pyrrolidin-2-one,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-benzyl]-imidazo[1,2-a]pyridine,(S)-5-{5-[4-(2H-Pyrazol-3-yl)-phenoxy]-indazol-1-ylmethyl}-pyrrolidin-2-one,2-Morpholin-4-ylmethyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-quinoline,3-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethyl}-oxazolidin-2-one,2-Methyl-6-[4-(2H-pyrazol-3-yl)-phenoxy]-3-pyrrolidin-1-ylmethyl-quinoline,2-Morpholin-4-ylmethyl-7-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridine,Morpholin-4-yl-{7-[4-(2H-pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-yl}-methanone,1-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethyl}-piperidine-4-carboxylicacid, and(R)-5-{6-[4-(2H-Pyrazol-3-yl)-phenoxy]-imidazo[1,2-a]pyridin-2-ylmethoxy}-piperidin-2-one,and pharmaceutically acceptable salts thereof.

In some embodiments, the LTA4H modulatory agent is a compound selectedfrom2-Hydroxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-ethanone,1-(4-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-ethanone,1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-azetidin-3-ol,2-Methoxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-ethanone,(S)-3-Hydroxy-1-(1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-4-yl)-pyrrolidin-2-one,3-(1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-4-yl)-oxazolidin-2-one,1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-4-ol,3-Methyl-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-azetidin-3-ol,2-Hydroxy-1-[(R)-3-(methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-amino)-pyrrolidin-1-yl]-ethanone,2-Hydroxy-1-[(S)-3-(methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-amino)-pyrrolidin-1-yl]-ethanone,2-Hydroxy-N-methyl-N—((S)-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrrolidin-3-yl)-acetamide,2-Hydroxy-N-methyl-N—((R)-1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrrolidin-3-yl)-acetamide,(S)-1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrrolidin-3-ol,1-(4-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-propan-1-one,2-Hydroxy-N-methyl-N-(1-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidin-4-yl)-acetamide,1-{3-[(Methyl-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-amino)-methyl]-azetidin-1-yl}-ethanone,(R)-1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-pyrrolidin-3-ol,(S)-2-Hydroxy-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-propan-1-one,1-{7-[5-(2H-Pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperidine-4-carboxylicacid dimethylamide,2-Hydroxy-2-methyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-propan-1-one,2,2-Dimethyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-propan-1-one,Cyclopropyl-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-methanone,and2-Methyl-1-(4-{7-[5-(2H-pyrazol-3-yl)-pyridin-2-yloxy]-quinolin-3-ylmethyl}-piperazin-1-yl)-propan-1-one,and pharmaceutically acceptable salts thereof.

In certain embodiments, the LTA4H modulatory agent is of the formula(XII):

or a pharmaceutically acceptable salt thereof,

where:

A³, A⁴ and A⁵ are each independently CH or N;

L¹ is a linker selected from —O— and —CH₂—;

L³ is absent or a —(C₁-C₆)alkylene-linker; wherein said—(C₁-C₆)alkylene-linker is optionally substituted with one to threegroups selected from —OH, halo, —(C₁-C₆)alkyl; D is a ring selected from

(a) —(C₃-C₇)cycloalkyl, (C₆-C₁₀)aryl, and -(5-to 11-membered)heteroaryl;

(b) -(4-to 11-membered)heterocycloalkyl, comprising an O or S ring atomand optionally 1 to 3 additional ring heteroatoms selected from N, O,and S;

(c) 4-8 member monocyclic heterocyclic comprising a N ring atom and 1 to3 additional ring heteroatoms selected from N, O, and S;

(d) a 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclicheterocyclic radical comprising a N ring atom and optionally 1 to 3additional ring heteroatoms selected from N, O, and S; and

(e) a group selected from 2-oxo-pyrrolidin-1-yl, 2-oxo-pyrrolidin-3-yl,2-oxo-pyrrolidin-5-yl, 1-methyl-2-oxo-pyrrolidin-4-yl, and2-oxo-piperidin-5-yl

wherein each of said D rings is optionally substituted with one to threeR¹ groups; and wherein each of said D rings is further optionallysubstituted, where possible, by one or two groups independently selectedfrom (═O) and (═S);

each R¹ is independently selected from halo, —OH, —CF₃, —CN,—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —C(O)R², —C(O)OR², —C(O)N(R²)₂, —N(R²)₂,—N(R²)C(O)R², —S(O)₂R², —N(R²)—S(O)₂—R², —(C₃-C₆)cycloalkyl, -(5-to11-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl; wherein each of said, —(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, -(5-to 11-membered)heterocycloalkyl,—(C₆-C₁₀)aryl, and -(5-to 11-membered)heteroaryl of said R¹ group isoptionally substituted with one to three groups selected from halo, —OH,—CF₃, —(C₁-C₆)alkyl, —C(O)OH, —C(O)OC₁-C₆)alkyl, —C(O)(C₁-C₆)alkyl),—NH₂, —NH(C₁-C₆)alkyl, N((C₁-C₆)alkyl)₂ and —CN;

each R² is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, -(5-to 11-membered)heterocycloalkyl,—(C₆-C₁₀)aryl, and -(5-to 11-membered)heteroaryl; wherein each of said,—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, -(5-to11-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl of said R² group is optionally independentlysubstituted by one to three groups selected from halo, —OH, —CF₃,—(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂ and —CN.

In some embodiments of formula (XII), L3-D taken together are describedby a group selected from (1-methyl-pyrrolidin-2-on-4-yl)methyl,(pyrrolidin-2-on-3yl)oxy, (pyrrolidin-2-on-5-yl)methyloxy,2-(pyrrolidin-2-on-1-yl)ethyloxy, 3-(pyrrolidin-2-on-1-yl)propyloxy,(tetrahydrofuran-3-yl)oxy, (tetrahydrofuran-2-yl)methyloxy,(tetrahydrofuran-3-yl)methyloxy; (piperidin-2-on-5-yl)oxy,(1,3-oxazolidin-2-on-4-yl)methyloxy,(1,3-oxazolidin-2-on-5-yl)methyloxy, (morpholin-3-yl)methyloxy,(morpholin-4-yl)ethyloxy, 1H-pyrazol-5-yl, (1H-pyrazol-5-yl)methyloxy,(1H-pyrazol-3-yl)methyloxy, (1-methyl-1H-pyrazol-3-yl)methyloxy,(1-methyl-1H-pyrazol-5-yl)methyloxy,(1-methyl-2-(2-furyl)-pyrazol-5-yl)methyloxy,3-(1H-pyrazol-1-yl)-ethyloxy, 2-(1H-pyrazol-4-yl)-ethyloxy,3-(1H-pyrazol-1-yl)-3-methylpropyloxy, (furan-2-yl)methyloxy,(furan-3-yl)methyloxy, (dihydrofuran-2(3H)-on-3-yl)oxy,(dihydrofuran-2(3H)-on-5-yl)methyloxy, (pyridin-3-yl)methyloxy,(pyridin-4-yl)methyloxy, (2-(1H-pyrazol-1-yl)-pyridin-5-yl)methyloxy,1-(pyridin2-yl)-ethyloxy, 2-(pyridin-2-yl)ethyloxy,2-(pyridin-3-yl)ethyloxy, 2-(pyridin-4-yl)-ethyloxy,(pyrimidin-2-yl)methyloxy, (thien-3-yl)methyloxy,2-(thien-2-yl)ethyloxy, (tetrahydro-2H-pyran-3-yl)oxy,(tetrahydro-2H-pyran-4-yl)oxy), (tetrahydro-2H-pyran-2-yl)methyloxy,(tetrahydro-2H-pyran-3-yl)methyloxy,(tetrahydro-2H-pyran-4-yl)methyloxy,2-(tetrahydro-2H-pyran-2-yl)ethyloxy,2-(tetrahydro-2H-pyran-4-yl)ethyloxy,(2-methyl-1H-imidazol-1-yl)ethyloxy, (pyrazin-2-yl)methyloxy, benzyloxy,(4-(methylsulfonyl)benzyl)oxy, (1,3-thiazol-2-yl)methyloxy,(1,3-thiazol-5-yl)methyloxy, 2-(1,3-thiazol-5-yl)ethyloxy,(4-methyl-1,2,3-thiadiazol-5-yl)methyloxy, (isoxazol-5-yl)methyloxy,2-(isoxazol-4-yl)ethyloxy, (1-methyl-1,2,4-triazol-5-yl)methyloxy,(1,3-oxazol-4-yl)methyloxy, (1,3-oxazol-5-yl)methyloxy,(2-methyl-1,3-oxazol-4-yl)methyloxy,(4-methyl-1,3-oxazol-5-yl)methyloxy, (1H-benzimidazol-2-yl)methyloxy,(1H-benzimidazol-5-yl)methyloxy, (1H-benzimidazol-1-yl)ethyloxy,(1H-benzimidazol-2-yl)ethyloxy,2-((1H-benzimidazol-2-yl)-amino)ethyloxy,(imidazo[2,1-b][1,3]thiazol-2-yl)methyloxy,(1H-pyrrolo[2,3-b]pyridin-5-yl)methyloxy,(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)oxy,2-(1H-pyrrolo[3,2-b]pyridin-6-yl)-ethyloxy,(imidazo[1,2-a]pyridin-2-yl)methyloxy, (1,3-benzothiazol-2-yl)methyloxy;and (imidazo[1,2-a]pyridin-6-yl)methyloxy.

In some embodiments the LTA4H modulatory agent includes an arylpyrazolesmall molecule described in any of U.S. Pat. Nos. 9,573,957; 9,403,830;9,303,018; and 9,139,567, each of which is incorporated herein byreference.

In some embodiments, the LTA4H modulatory agent is a benzodioxane, or apharmaceutically acceptable salt thereof. In certain embodiments, theLTA4H modulatory agent is of the formula (XIII):

where:

X^(a) is N or CH;

n is an integer from 0 to 3;

R⁴² is selected from halo, —OH, —CN, —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, and—(C₃-C₆)cycloalkyl;

R⁴⁰ and R⁴¹ are each independently selected from —H and —(C₁-C₆)alkyl;wherein R⁴⁰ and R⁴¹ may join to form a 3-to 6-membered ring optionallycomprising one to three heteroatoms, and further optionally substitutedwith one to three groups selected from halo, —OH, (═O), —(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —C(O)O—H, —C(O)(C₁-C₆)alkyl, and —C(O)NH₂;

A is a group of formula —NR⁴³R⁴⁴, wherein R⁴³ and R⁴⁴ are eachindependently selected from —H, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,-(4-to 14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, -(4-to 14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl,and -(5-to 11-membered)heteroaryl of said R⁴ and R⁵ groups is optionallyindependently substituted by one to three R⁶ groups; wherein two R⁶groups when attached to the same carbon atom of said —(C₁-C₆)alkyl mayjoin to form a 3-to 6-membered ring optionally comprising one to threeheteroatoms, and further optionally substituted with one to three groupsselected from halo, —OH, (═O), —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —C(O)O—H,—C(O)(C₁-C₆)alkyl, and —C(O)NH₂;

A is a (4-to 14-membered)N-heterocyclic ring of formula B:

wherein said ring B is:

(a) a non-aromatic 4-8 membered monocyclic radical; or

(b) a bridged bicyclic radical, a spirocyclic radical, or a 6 to11-membered fused bicyclic radical, wherein each of said bridgedbicyclic radical, spirocyclic radical, and 6 to 11-membered fusedbicyclic radical comprises at least a nonaromatic N-heterocyclic ringwhich is attached to the carbon atom 1 of the compound of formula (I);wherein each of said bridged bicyclic radical, spirocyclic radical, and6 to 11-membered fused bicyclic radical may optionally comprise anaromatic ring;

wherein said ring B may additionally comprise one to three additionalring heteroatoms independently selected from N, O and S;

wherein said ring B may be further optionally substituted by one tothree groups selected from halo, —OH, (═O), —C(O)O—H,—C(O)O—(C₁-C₆)alkyl, and —(C₁-C₆)alkyl; and

wherein L is absent or a linker selected from —(C₁-C₆)alkylene-;

each R⁶ is independently selected from halo, —OR⁷, —CF₃, —CN,—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl, —C(O)R⁷, —C(O)₂R⁷, —C(O)N(R⁷)₂, —N(R⁷)₂,—NHC(O)R⁷, —NHC(O)N(R⁷)₂, —S(O)₂R⁷, —NH—S(O)₂—R⁷, —(C₃-C₆)cycloalkyl,-(4-to 14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl; wherein each of said, —(C₁-C₆)alkyl,—O(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, -(4- to14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl of said R⁶ group is optionally substituted wherepossible with one to three groups selected from halo, —OH, —CF₃, —CN,(═O), —(C₁-C₆)alkyl, —C(O)O—H, —C(O)O—(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, —S(O)₂(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, -(4-to 14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl,and -(5-to 11-membered)heteroaryl; and

each R⁷ is independently selected from —H, —(C₁-C₆)alkyl,—(C₁-C₆)alkyl-OH, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl, —(C₃-C₆)cycloalkyl-OH, -(4-to14-membered)heterocycloalkyl, —(C₆-C₁₀)aryl, and -(5-to11-membered)heteroaryl; wherein each of said R⁷ group is optionallysubstituted where possible with a group selected from —OH,—NH(C₁-C₆)alkyl, —NHC(O)(C₁-C₆)alkyl, —C(O)NH₂, —S(O)₂(C₁-C₆)alkyl, and-(4-to 14-membered)heterocycloalkyl; wherein said -(4-to14-membered)heterocycloalkyl group is optionally substituted wherepossible with a (═O) group.

In some embodiments, the LTA4H modulatory agent is a compound selectedfrom3-[(4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperazin-1-yl)methyl]benzoicacid,7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylicacid ethyl ester,7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylicacid amide,7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylicacid methylamide,7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine-2-carboxylicacid amide,7-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine-2-carboxylicacid methylamide,6-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-4H-1,2,3a,6-tetraaza-azulene-3-carboxylicacid amide,6-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-4H-1,2,3a,6-tetraaza-azulene-3-carboxylicacid methylamide,[(1a,5a,6a)-3-[(S)-4-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylicacid ((S)-2-hydroxy-propyl)-amide,[(1α,5α,6α)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylicacid ((S)-2-hydroxy-1-methyl-ethyl)-amide,7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine-3-carbonitrile,N-{(1a,5a,6a)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-acetamide,[(1a,5a,6a)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid (2-hydroxy-2-methyl-propyl)]-amide,N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-2-methoxy-acetamide,1-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazin-1-yl}-2-hydroxy-ethanone,4-{1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azetidin-3-yl}-benzoicacid,1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylicacid (2-hydroxy-2-methyl-propyl)-amide,1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-methanesulfonyl-ethanone,1-{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-[1,4]diazepan-1-yl}-2-methoxy-ethanone,5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine,{(endo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea,2-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-N-methoxy-acetamide,(R)—N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-2-methylamino-propionamide,N—{C1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-ylmethyl}-2-hydroxy-2-methyl-propionamide,N-{(1a,5a,6a)-3-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylmethyl}-methanesulfonamide,1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.2]oct-2-yl}-ethanone,4-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-cyclohexanecarboxylicacid,1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azepane-4-carboxylicacid,[(1a,5a,6a)-3-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hexane]-6-carboxylicacid,(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide,1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-phenyl-piperidin-4-ol,1-{5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-ethanone,1-{8-[(S)-4-(2,3-Dihydro-[,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-3-yl}-ethanone,5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide,{(exo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea,2-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yloxy}-acetamide,(S)-3-[4-(1,1-Dioxo-1lambda6-[1,4]thiazepan-4-ylmethyl)-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine,1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-methyl-piperidin-4-ol,1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone,N-{(endo)-8-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide,N-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-ylmethyl}-acetamide,[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-(1,1-dioxo-tetrahydro-1lambda-6-thiophen-3-yl)-methyl-amine, 1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.2]oct-2-yl}-2-hydroxy-ethanone,{1-[(S)-4-(2,3-dihydro-[1,4]dioxino-[2,3-b]pyridin-3-yl)-benzyl]-spiro-[3H-indole-3,4′-piperidine]-1(2H)-urea,{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-ylmethyl}-urea,{4-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperazin-1-yl}-acetonitrile,(R)-7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahydro-oxazolo[3,4-a]pyrazin-3-one,{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-(3-hydroxy-azetidin-1-yl)-methanone,1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidine-4-carboxylicacid [(S)-1-(tetrahydro-furan-2-yl)methyl]-amide,N-[3-[4-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]methyl]piperazin-1-yl]-3-oxo-propyl]acetamide,N-[1-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]-2-(2-oxopyrrolidin-1-yl)acetamide,N-[1-[[4-[(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]tetrahydropyran-4-carboxamide,3-{1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-piperidin-4-yl}-[1,3]oxazinan-2-one,1-{(1S,4S)-5-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone,(S)-3-{4-[4-(Pyridin-3-yloxy)-piperidin-1-ylmethyl]-phenyl}-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine,1-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-4-phenyl-piperidine-4-carboxylicacid, (S)-3-[4-(1-Oxo-1lambda4-thiomorpholin-4-ylmethyl)-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine,and(S)-7-[(S)-4-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-hexahydro-oxazolo[3,4-a]pyrazin-3-one.

In some embodiments, the LTA4H modulatory agent is a compound selectedfrom 1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidine,4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]morpholine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4,4-dimethylpiperidine,8-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2,8-diazaspiro[4,5]decan-1-one,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-fluoropiperidine,(1s,4s)-7-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-7-azabicyclo[2.2.1]heptane,4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]thiomorpholine1,1-dioxide,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N-dimethylpiperidine-4-carboxamide,(3S)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidin-3-ol,1-({1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-3-yl}methyl)pyrrolidin-2-one,1-{4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperazin-1-yl}ethenone,2-{[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]amino}-1-(pyrrolidin-1-yl)ethenone,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methyl-1-(methylsulfonyl)piperidin-4-amine,1-{4-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino]piperidin-1-yl}ethenone,3-[4-(pyrrolidin-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,7-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine,3-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-3-carboxylicacid,(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-3-carboxylicacid,1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2,2,2-trifluoroethanol,2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methylpropan-2-amine,(2R)—N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]butan-2-amine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-methylpiperidine-4-carboxamide,4-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}butanoicacid,{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methanol,2-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}propan-2-ol,3-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}propan-1-ol,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-methyl-1,4-diazepane,1-{4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,4-diazepan-1-yl}ethenone,4-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,4-oxazepane,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methoxy-N-methylethanamine,(3R)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidin-3-ol,8-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-methoxyazetidine,{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}(morpholin-4-yl)methanone,2-(1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}-N,N-dimethylacetamide,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-(methylsulfonyl)piperidine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]azepane,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]cyclopentanamine,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-methyl-2-(pyridin-2-yl)ethanamine,1-cyclopropyl-N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]methanamine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-4-phenylpiperidin-4-ol,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-ethylethanamine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]azetidine-3-carbonitrile,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-methoxypyrrolidine,N-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methanesulfonamide,N-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-2-methyl-1-(pyrrolidin-1-yl)propan-2-amine,1-({1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}methyl)pyrrolidin-2-one,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N,N-dimethylpiperidine-4-carboxamide,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-N-(2-hydroxyethyl)piperidine-4-carboxamide,1-{1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidin-4-yl}urea,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)phenyl]-Nyridin-3-ylmethyl)methanamine,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]methanamine,2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroisoquinoline-4-carboxylicacid,(1R,3S)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanecarboxylicacid,3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)-4,4-dimethylpentanoicacid,1-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanecarboxylicacid,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylglycine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-carboxylicacid,trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanecarboxylicacid,cis-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanecarboxylicacid,1-[(3R)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)pyrrolidin-1-yl]ethenone,1-[(3S)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)pyrrolidin-1-yl]ethenone,trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanecarboxamide,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylcyclohexanamine,(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl)methanol,2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)ethanol,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}propan-2-amine,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-methoxypropan-2-amine,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}propan-1-amine,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylethanamine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}-N,N-dimethylmethanamine,trans-4-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanol,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-ol,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N′,N′-trimethylethane-1,2-diamine,2-(cyclohexyl{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)ethanol,(1R,2R,4S)—N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}bicyclo[2.2.1]heptan-2-amine,(4aR,8aS)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}decahydroquinoline,(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanecarboxamide,[(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexyl]methanol,(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-ol,[(1R,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexyl]methanol,(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methanol,(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-ol,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}imidazolidin-4-one,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,N-dimethylpyrrolidin-3-amine,1′-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,4′-bipiperidin-2-one,N-(cyclopropylmethyl)-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}cyclohexanamine,(1R,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclohexanol,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methoxypiperidine,1-[(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methyl]pyrrolidin-2-one,trans-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methylcyclohexanamine,(1S,2R)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanol,(1S,2S)-2-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanol,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}tetrahydro-2H-pyran-3-amine,(1S,2S)-2-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino]cyclohexanol,(1R,2S)-2-[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(methyl)amino]cyclohexanol,4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-3-methylmorpholine,5-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)-1-methylpiperidin-2-one,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,1-dimethylpiperidin-4-amine,4-[({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)methyl]phenol,2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidine-3-carboxylicacid,1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]piperidine-3-carboxamide,(3S)-1-[4-(2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]-3-fluoropyrrolidine,9-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,9-diazaspiro[5.5]undecan-1-one,1-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]non-1-yl)ethenone,9-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methyl-2,9-diazaspiro[5.5]undecan-1-one,8-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methyl-2,8-diazaspiro[4.5]decan-1-one,7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-(methylsulfonyl)-1,7-diazaspiro[4.4]nonane,2-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]non-1-yl)acetamide,(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]non-1-yl)acetonitrile,1-(7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]non-1-yl)-2-methoxyethanone,9-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-2-methyl-2,9-diaza-spiro[5.5]undecan-1-one,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,4-diazepan-5-one,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,4-diazepan-5-one,N-[2-({4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}amino)ethyl]acetamide,3-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)propanoicacid,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}cyclopentanamine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylethanamine,(3S)-3-{4-[(1s,4s)-7-azabicyclo[2.2.1]hept-7-ylmethyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,(3S)-1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyrrolidin-3-ol,4-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)butanoicacid,1-[4-({4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}amino)piperidin-1-yl]ethenone,(3S)-3-{4-(5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-ylmethyl)phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,(3S)-3-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazine-1-carboxamide,(3S)-3-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-1-(methylsulfonyl)piperidin-4-amine,(3S)-3-(4-{[4-(2-methoxyethoxyl)piperidin-1-yl]methyl}phenyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,2-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-N,N-dimethylacetamide,(3S)-3-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}cyclobutanamine,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1-(methylsulfonyl)piperidin-4-amine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carbonitrile,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)acetamide,[(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]aceticacid,[(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl]aceticacid,1-(4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazin-1-yl)ethenone,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-ol,1-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)urea,(3S)-3-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carboxylicacid,(1S,3R)-3-({4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)cyclopentanecarboxylicacid, 1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-ol,1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-ol,8-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[4.5]decan-1-one,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine,1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine,4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}morpholine,4-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}morpholine,1-{4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylicacid, 4-[4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]morpholine,1-[4-(7-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl)benzyl]pyrrolidine,(3R)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,1-{4-[(3R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carboxamide,1-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)benzyl]pyrrolidin-2-one,3-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)benzyl]-1,3-oxazolidin-2-one,1-[4-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl)phenyl]methanamine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-methylpiperidine-4-carboxylicacid,(3R,4R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-3-methylpiperidine-4-carboxylicacid,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-fluoropiperidine-4-carboxylicacid,(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-carboxylicacid,(3S)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidine-3-carboxylicacid,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-(1H-tetrazol-5-yl)piperidine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-amine,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-hydroxyacetamide,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-methoxyacetamide,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-hydroxy-2-methylpropanamide,1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)pyrrolidine,4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)morpholine,1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]phenyl}ethyl)piperidine-4-carboxylicacid,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-4-methylpiperidine-4-carboxylicacid,2-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)-2-methylpropanoicacid,2-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2-methylpropanoicacid,2-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid,4-{[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(ethyl)amino]methyl}benzoicacid, 4-[(butyl{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}amino)methyl]benzoicacid,3-{[{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}(ethyl)amino]methyl}benzoicacid, and3-[(4-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperazin-1-yl)methyl]benzoicacid, or a pharmaceutically salt thereof of each of the foregoing.

In some embodiments, the LTA4H modulatory agent is a compound selectedfrom4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)butanoicacid,4-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)benzoicacid,(3S)-3-{4-[(1s,4s)-7-azabicyclo[2.2.1]hept-7-ylmethyl]phenyl}-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)methanesulfonamide,(3S)-3-[4-(azepan-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methylpiperidine,7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]nonane-1-carboxamide,7-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,7-diazaspiro[4.4]nonan-2-one,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylicacid,(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)(morpholin-4-yl)methanone,8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,3,8-triazaspiro[4.5]decane-2,4-dione,(3S)-3-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino{2,3-b}pyridine,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl)-N-methylacetamide,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-4-(1,1-dioxido-1,2-thiazolidin-2-yl)piperidine,(3R)-1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}pyrrolidin-3-ol,N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2-hydroxyacetamide,4-{(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)methyl}benzoicacid,(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)(morpholin-4-yl)methanone,(3S)-3-[4-(morpholin-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,8-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2,8-diazaspiro[4.5]decan-1-one,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carbonitrile,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-methylpiperidine-4-carboxamide,8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2,8-diazaspiro[4.5]decan-1-one,N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)-2-hydroxy-2-methylpropanamide,N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl-1-hydroxycyclopropanecarboxamide,N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-ethylcyclopentanamine,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylpiperidine-4-carboxamide,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methylcyclopentanamine,1-{(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-3-yl)methyl}pyrrolidin-2-one,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-2-methylpyrrolidine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-1-(pyrrolidin-1-yl)propan-2-amine,N-cyclohexyl-N-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N′,N′-dimethylethane-1,2-diamine,N-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)acetamide,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-methyl-2-(pyridin-2-yl)ethanamine,(3S)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-3-carboxamide,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidine-4-carboxamide,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}pyrrolidin-3-yl)acetamide,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-(2-hydroxyethyl)piperidine-4-carboxamide,(3S)-3-[4-(1,4-oxazepan-4-ylmethyl)phenyl]-2,3-dihydro[1,4]dioxino[2,3-b]pyridine,1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N-(2-hydroxyethyl)piperidine-4-carboxamide,4-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)benzoicacid,1-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)urea,7-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-1,7-diazaspiro[4.4]nonan-2-one,8-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-2-methyl-2,8-diazaspiro[4.5]decan-1-one,1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-ol,N-(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl)methanesulfonamide,3-(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl)propan-1-ol,(3S)-3-{4-[(4-methylpiperidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino{2,3-b}pyridine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-N-ethylethanamine,N-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1-(methylsulfonyl)piperidin-4-amine,(3S)-3-{4-[(4-fluoropiperidin-1-yl-methyl]phenyl}-2,3-dihydro[1,4]dioxino{2,3-b}pyridine,1-(4-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}-1,4-diazepan-1-yl)ethenone,[(3R)-1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]aceticacid,(1-{4-[(3S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperidin-4-yl-methanol,4-[(1-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-4-yl-methyl]benzoicacid,(3S)-3-{4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino{2,3-b}pyridine,(3S)-3-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-2,3-dihydro[1,4]dioxino{2,3-b}pyridine, andN-{4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-yl]benzyl}-N,2-dimethylpropan-2-amine,or a pharmaceutically salt thereof of each of the foregoing.

In some embodiments, the LTA4H modulatory agent is4-{4-[(3S)-2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzyl}piperazine-1-carboxamide,or a pharmaceutically acceptable salt thereof. In some embodiments, theLTA4H modulatory agent is4-{4-[(3S)-2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-yl]benzy}piperazine-1-carboxamide.In some cases, the LTA4H modulatory agent is1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylicacid, or a pharmaceutically acceptable salt thereof. In some cases, theLTA4H modulatory agent is1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidine-4-carboxylicacid. In some cases, the LTA4H modulatory agent is[(3R)-1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]aceticacid, or a pharmaceutically acceptable salt thereof. In some cases, theLTA4H modulatory agent is[(3R)-1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-yl]benzyl}piperidin-3-yl]aceticacid.

In some embodiments the LTA4H modulatory agent includes an benzodioxanesmall molecule described in any of U.S. Pat. Nos. 9,133,146; 8,551,982;8,946,203; 9,133,146 and 9,662,339; each of which is incorporated hereinby reference.

In some embodiments, the LTA4H modulatory agent is a biarylamide, or apharmaceutically acceptable salt thereof. In certain embodiments, theLTA4H modulatory agent is of the formula (XIX):

or a pharmaceutically acceptable salt thereof, wherein:

A is selected from pyrazolyl, imidazolyl, pyrrolyl, thienyl, thiazolyl,triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,pyrrolopyridinyl, dihydropyrrolopyridinyl, imidazopyridinyl,pyrazolopyridinyl and quinolinyl;

B is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl;

C is pyridinyl;

R^(1a) and R^(1b) are each independently selected from —H, C1-6 alkyl,C₁₋₃alkoxyl, —C₁₋₃ alkyl-OH, hydroxy, —C(O)—C₁₋₃ alkyl and —NR⁵R⁶;

R² and R³ together with the carbon atom to which they are attached forma cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl ora tetrahydropyranyl ring;

R^(4a) and R^(4b) are each independently selected from —H, C₁₋₃ alkyl,C₁₋₃alkoxyl, —C₁₋₃ alkyl-OH, phenyl, —O-phenyl, thiazolyl, oxazolyl,isoxazolyl, furanyl, thienyl, pyrrolyl, thiadiazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopropyl,cyclopbutyl, cyclopenyl, cyclohexyl, pyrrolidinyl, tetrahydrothienyl,piperidinyl, piperazinyl, morpholinyl, —C₁₋₃alkyl-phenyl, —C₁₋₃alkyl-pyridinyl, —C₁₋₃ alkyl-pyrimidinyl, —C₁₋₃ alkyl-pyridazinyl, —C₁₋₃alkyl-pyrazinyl, —C₁₋₃ alkyl-heterocyclyl, —O—C₁₋₃ alkyl-phenyl, —O—C₁₋₃alkyl-pyridinyl, —OC₁₋₃ alkyl, CF₃, O—CF₃, —COOR⁵, —C(O) C₁₋₃alkyl-S(O)₂—NR⁵R⁶, —S(O)₂CF₃, —S(O)₂C₁₋₃ alkyl, —C(O) NR⁷R⁸, hydroxy,halogen, and cyano, wherein each group is optionally independentlysubstituted with 1-3 substituents chosen from C₁₋₆ alkyl, C₁₋₆ alkoxyl,hydroxy and halogen;

R⁵ and R⁶ are each independently chosen from H, C₁₋₅ alkyl,—C₁₋₃alkylhydroxy and C₁₋₃ alkyl-O—C₁₋₃ alkyl;

or, R⁵ and R⁶ together with the nitrogen atom to which they are attachedform a piperidinyl, morpholinyl or thiomorpholinyl ring;

R⁷ and R⁸ are each independently chosen from H, C₁₋₆ alkyl, —S(O)₂C₁₋₃alkyl, and —C(NH)—NH₂.

In some embodiments the LTA4H modulatory agent includes a biarylamidesmall molecule described in U.S. Pat. No. 9,073,895, which isincorporated herein by reference.

In some instances, the LTA4H modulatory agent is not a compounddisclosed in U.S. Pat. Nos. 8,569,303; 9,822,106; 9,856,249; 9,777,006;and 9,856,249; or United States Published Patent Application PublicationNos. 20180118735; 20180162854 and 20180162854.

In some cases, the modulating agent exhibits an affinity (Kd) for LTA4Hthat is sufficient to provide for the desired modulation of LTA4H. Theaffinity of the agent can be at least 1-fold greater, at least 2-foldgreater, at least 3-fold greater, at least 4-fold greater, at least5-fold greater, at least 6-fold greater, at least 7-fold greater, atleast 8-fold greater, at least 9-fold greater, at least 10-fold greater,at least 20-fold greater, at least 30-fold greater, at least 40-foldgreater, at least 50-fold greater, at least 60-fold greater, at least70-fold greater, at least 80-fold greater, at least 90-fold greater, atleast 100-fold greater, or at least 1000-fold greater, or more, than theaffinity of the agent for unrelated transporter. In some cases, theaffinity of an agent to LTA4H can be, for example, from about 100nanomolar (nM) to about 1 nM, from about 100 nanomolar (nM) to about 0.1nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM toabout 1 femtomolar (fM), or from about 10 nanomolar (nM) to about 0.1nM. In some embodiments, the affinity between the agent and LTA4H ischaracterized by a Kd (dissociation constant) of 10⁻⁶ M or less, such as10⁻⁷ M or less, including 10⁻⁸ M or less, e.g., 10⁻⁹ M or less, 10⁻¹⁰ Mor less, 10⁻¹¹ M or less, 10−⁻¹² M or less, 10⁻¹³ M or less, 10⁻¹⁴ M orless, including 10⁻¹⁵ M or less. Modulating agents include antibodiesthat specifically bind to LTA4H. In some cases, the antibodyspecifically binds an epitope of LTA4H that provides for inhibition ofthe function of LTA4H. Antibodies that can be used as modulating agentsin connection with the present disclosure can encompass, but are notlimited to, monoclonal antibodies, polyclonal antibodies, bispecificantibodies, Fab antibody fragments, F(ab)2 antibody fragments, Fvantibody fragments (e.g., VH or VL), single chain Fv antibody fragmentsand dsFv antibody fragments. Furthermore, the antibody molecules can befully human antibodies, humanized antibodies, or chimeric antibodies.The antibodies that can be used in connection with the presentdisclosure can include any antibody variable region, mature orunprocessed, linked to any immunoglobulin constant region. Minorvariations in the amino acid sequences of antibodies or immunoglobulinmolecules are encompassed by the present disclosure, providing that thevariations in the amino acid sequence maintain 75% or more, e.g., 80% ormore, 90% or more, 95% or more, or 99% or more of the sequence. Inparticular, conservative amino acid replacements are contemplated.

Conservative replacements are those that take place within a family ofamino acids that are related in their side chains. Whether an amino acidchange results in a functional peptide can be determined by assaying thespecific activity of the polypeptide derivative. “Antibody fragments”comprise a portion of an intact antibody, for example, the antigenbinding or variable region of the intact antibody. Examples of antibodyfragments include Fab, Fab′, F(ab′)2, and Fv fragments; diabodies;linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062 (1995));single-chain antibody molecules; and multispecific antibodies formedfrom antibody fragments. Papain digestion of antibodies produces twoidentical antigen-binding fragments, called “Fab” fragments, each with asingle antigen-binding site, and a residual “Fc” fragment, a designationreflecting the ability to crystallize readily. Pepsin treatment yieldsan F(ab′)2 fragment that has two antigen-combining sites and is stillcapable of cross-linking antigen. Antibodies that can be used inconnection with the present disclosure thus can encompass monoclonalantibodies, polyclonal antibodies, bispecific antibodies, Fab antibodyfragments, F(ab)2 antibody fragments, Fv antibody fragments (e.g., VH orVL), single chain Fv antibody fragments and dsFv antibody fragments.Furthermore, the antibody molecules can be fully human antibodies,humanized antibodies, or chimeric antibodies. In some embodiments, theantibody molecules are monoclonal, fully human antibodies. Theantibodies that can be used in connection with the present disclosurecan include any antibody variable region, mature or unprocessed, linkedto any immunoglobulin constant region. If a light chain variable regionis linked to a constant region, it can be a kappa chain constant region.If a heavy chain variable region is linked to a constant region, it canbe a human gamma 1, gamma 2, gamma 3 or gamma 4 constant region, morepreferably, gamma 1, gamma 2 or gamma 4 and even more preferably gamma 1or gamma 4. As such, additional LTA4H modulatory agents includeantibodies, including monoclonal antibodies, which selectively bind tothe LTA4H enzyme to modulate its activity. Such antibodies may reduceone or more of the LTA4H enzyme's activities including, for example, itsepoxide hydrolase and/or aminopeptidase activities.

In some instances, the agent modulates the activity of a LTA4H followingexpression, such that the agent is one that changes the activity of theprotein encoded by the target gene following expression of the proteinfrom the target gene. In other embodiments, the modulating agentmodulates expression of the RNA and/or protein from the gene encodingthe LTA4H, such that it changes the expression of the RNA or proteinfrom the target gene in some manner. In these instances, the agent maychange expression of the RNA or protein in a number of different ways.As would be readily understood by one of ordinary skill in the art, onecan reduce expression (protein production) of an endogenous gene at theDNA, RNA, or protein level. For example, expression can be reduced byreducing the total amount of wild type protein made by the endogenouslocus, and this can be accomplished either by changing the nature of theprotein produced (e.g., via gene mutation to generate a loss of functionallele such as a null allele or an allele that encodes a protein reducedfunction) or by reducing the overall levels of protein produced withoutchanging the nature of the protein itself. In certain embodiments, theagent is one that reduces, including inhibits, expression of functionalLTA4H. Inhibition of protein expression may be accomplished using anyconvenient means, and one of ordinary skill in the art will be aware ofmultiple suitable methods. For example, in order to reduce/inhibitexpression, one can reduce protein levels post-translationally; one canblock production of protein by blocking/reducing translation of mRNA(e.g., using an RNAi agent such as an shRNA or siRNA that targets themRNA of an endogenous gene); one can reduce mRNA levelspost-transcriptionally (e.g., using an RNAi agent such as an shRNA orsiRNA that targets the mRNA of an endogenous gene); one can reduce mRNAlevels by blocking transcription (e.g., using gene editing tools toeither alter a promoter and/or enhancer sequence or to modulatetranscription, or by using modified gene editing tools, e.g., CRISPRi,that can modify transcription without cutting the target DNA).Additionally, one can alter the nature of the protein made from anendogenous locus by inducing (e.g., using gene editing technology) aloss of function mutation, which can range from an allele with reducedwild type activity to a dead protein or no protein (e.g., catalyticallyinactive mutant, a frameshift allele, a gene knockout, etc.). Moreover,one can reduce mRNA levels via gene editing methods that result in lownet transcript levels (e.g., frameshift mutations can trigger nonsensemediated mRNA decay). Any convenient inhibitor of expression can beutilized as an antagonist in the subject methods. Such antagonists canact to inhibit expression at a transcriptional, translational, orpost-translational level. In some embodiments, the inhibitors arenucleic-acid based, including, without limitation, DNA, RNA, chimericRNA/DNA, protein nucleic acid, and other nucleic acid derivatives. Insome embodiments, the expression inhibitors encompass RNA moleculescapable of inhibiting receptor production when introduced into areceptor-expressing cell (termed RNAi), including short hairpindouble-stranded RNA (shRNA). In some instances, the expressioninhibitors are small interfering RNA (siRNA). In some instances, theexpression inhibitors are small interfering microRNA. It will beunderstood that any sequence capable of reducing the cell surfaceexpression of a receptor, or reducing the expression of a receptorligand, can be used in practicing the methods of the present disclosure.Examples of agents that inhibit expression of an endogenous gene (.g.,as described herein) include but are not limited to: (a) an RNAi agentsuch as an shRNA or siRNA that specifically targets mRNA encoded by theendogenous gene; (b) a genome editing agent (e.g., a Zinc fingernuclease, a TALEN, a CRISPR/Cas genome editing agent such as Cas9, Cpf1,CasX, CasY, and the like) that cleaves the target cell's genomic DNA ata locus encoding the endogenous gene (e.g., SLC19A1)—thus inducing agenome editing event (e.g., null allele, partial loss of functionallele) at the locus of the endogenous gene; (c) a modified genomeediting agent such as a nuclease dead zinc finger, TALE, or CRISPR/Casnuclease fused to a transcriptional repressor protein that modulates(e.g. reduces) transcription at the locus encoding the endogenous gene(e.g., SLC19A1) (see, e.g., Qi et al., Cell. 2013 Feb. 28;152(5):1173-83′; Gilbert et al, Cell. 2014 Oct. 23; 159(3):647-61;Larson et al., Nat Protoc. 2013 November; 8(11):2180-96). Examples ofagents that increase or activate expression of an endogenous gene (e.g.,as described herein) include, but are not limited to, CRISPR activation(CRISPRa) agents. When the agent is a CRISPR/Cas editing agent, theagent can include both the protein and guide RNA component. The guidenucleic acid (e.g., guide RNA) can be introduced into the cell as an RNAor as a DNA encoding the RNA (e.g., encoded by a DNA vector—on aplasmid, virus, and the like). The CRISPR/Cas protein can be introducedinto the cell as a protein or as a nucleic acid (mRNA or DNA) encodingthe protein. Programmable gene editing agents and their guide nucleicacids include, but are not limited to, CRISPR/Cas RNa-guided proteinssuch as Cas9, CasX, CasY, and Cpf1, Zinc finger proteins such as Zincfinger nucleases, TALE proteins such as TALENs, CRISPR/Cas guide RNAs,and the like. Antisense molecules can be used to down-regulateexpression of a target gene in the cell. The anti-sense reagent may beantisense oligodeoxynucleotides (ODN), particularly synthetic ODN havingchemical modifications from native nucleic acids, or nucleic acidconstructs that express such anti-sense molecules as RNA. The antisensesequence is complementary to the mRNA of the targeted protein, andinhibits expression of the targeted protein. Antisense molecules inhibitgene expression through various mechanisms, e.g., by reducing the amountof mRNA available for translation, through activation of RNAse H, orsteric hindrance. One or a combination of antisense molecules may beadministered, where a combination may include multiple differentsequences. Antisense oligonucleotides may be chemically synthesized bymethods known in the art (see Wagner et al. (1993), supra, and Milliganet al., supra.) Oligonucleotides may be chemically modified from thenative phosphodiester structure, in order to increase theirintracellular stability and binding affinity. A number of suchmodifications have been described in the literature, which alter thechemistry of the backbone, sugars or heterocyclic bases.

As an alternative to anti-sense inhibitors, catalytic nucleic acidcompounds, e.g. ribozymes, anti-sense conjugates, etc. may be used toinhibit gene expression. Ribozymes may be synthesized in vitro andadministered to the patient, or may be encoded on an expression vector,from which the ribozyme is synthesized in the targeted cell (forexample, see International patent application WO 9523225, and Beigelmanet al. (1995), Nucl. Acids Res. 23:4434-42). In addition, thetranscription level of a protein can be regulated by gene silencingusing RNAi agents, e.g., double-strand RNA (Sharp (1999) Genes andDevelopment 13: 139-141). RNAi, such as double-stranded RNA interference(dsRNAi) or small interfering RNA (siRNA), has been extensivelydocumented in the nematode C. elegans (Fire, A., et al, Nature, 391,806-811, 1998) and routinely used to “knock down” genes in varioussystems. RNAi agents may be dsRNA or a transcriptional template of theinterfering ribonucleic acid that can be used to produce dsRNA in acell. A number of options can be utilized to deliver the dsRNA into acell or population of cells such as in a cell culture, tissue, organ orembryo. For instance, RNA can be directly introduced intracellularly.Various physical methods are generally utilized in such instances, suchas administration by microinjection (see, e.g., Zernicka-Goetz, et al.(1997) Development 124:1133-1137; and Wianny, et al. (1998) Chromosoma107: 430-439). Other options for cellular delivery includepermeabilizing the cell membrane and electroporation in the presence ofthe dsRNA, liposome-mediated transfection, or transfection usingchemicals such as calcium phosphate. A number of established genetherapy techniques can also be utilized to introduce the dsRNA into acell. By introducing a viral construct within a viral particle, forinstance, one can achieve efficient introduction of an expressionconstruct into the cell and transcription of the RNA encoded by theconstruct. As such, other embodiments of the LTA4H modulatory agentsinclude siRNA or other agents which reduce the translation of LTA4H mRNAinto active protein enzyme form. Additional embodiments of the inventioninclude small molecule antagonists, antibodies, and mRNA reducing agents(e.g. siRNA) against the LTB₄ receptor(s).

The LTA4H enzyme protein level may be reduced using any convenientprotocol. In some instances, the LTA4H level is reduced by removingsystemic LTA4H from a subject, e.g., by removing LTA4H from thecirculatory system of the subject. In such instances, any convenientprotocol for removing circulatory LTA4H may be employed. For example,blood may be obtained from the subject and extra-corporeally processedto remove LTA4H from the blood to produce LTA4H-depleted blood. Theresultant LTA4H-depleted blood may then be returned to the subject. Suchprotocols may employ a variety of different techniques in order toremove LTA4H from the obtained blood. For example, the obtained bloodmay be contacted with a filtering component, e.g., a membrane, etc.,which allows passage of LTA4H but inhibits passage of other bloodcomponents, e.g. cells, etc. In some instances, the obtained blood maybe contacted with a LTA4H absorptive component, e.g., porous bead orparticulate composition, which absorbs LTA4H from the blood. In yetother instances, the obtained blood may be contacted with a LTA4Hbinding member stably associated with a solid support, such that LTA4Hbinds to the binding member and is thereby immobilized on the solidsupport, thereby providing for separation of LTA4H from other bloodconstituents. The protocol employed may or may not be configured toselectively remove LTA4H from the obtained blood, as desired. A numberof different technologies are known for removing specific proteins fromblood, and may be employed in embodiments of the invention, where suchtechnologies include those described in U.S. Pat. Nos. 5,240,614;6,416,487; 6,419,830; 6,423,024; 6,855,121; 7,066,900; 8,211,310;8,349,550; as well as published PCT Application Publication No.:WO/2003/020403; the disclosures of which applications are hereinincorporated by reference.

D. Administration

Aspects of the methods of the inventions described herein includetreatment of a subject with an LTA4H modulatory agent, e.g., asdescribed above. One of skill in the art would recognize that methods oftreatment of subjects with an LTA4H modulatory agent are recognized inthe art.

An embodiment of the invention includes treating a subject diagnosedwith a cognitive or motor impairment, or neuroinflammation byadministering to the subject an effective amount of an LTA4H modulatoryagent. Another embodiment of the invention includes administering theeffective amount of an LTA4H modulatory agent and subsequentlymonitoring the subject for improved cognitive or motor function, or areduction in neuroinflammation or increase in neurogenesis.

Biochemically, by an “effective amount” or “effective dose” of activeagent is meant an amount of active agent that will inhibit, antagonize,decrease, reduce, or suppress by about 20% or more, e.g., by 30% ormore, by 40% or more, or by 50% or more, in some instances by 60% ormore, by 70% or more, by 80% or more, or by 90% or more, in some casesby about 100%, i.e., to negligible amounts, and in some instances,reverse the progression of the cognitive impairment, age-associateddementia, motor disfunction, or neuroinflammation.

E. Indications

The subject methods and LTA4H modulatory agent(s) find use in treating,including preventing, aging-associated conditions, such as impairmentsin the cognitive ability of individuals, e.g., cognitive disorders,including (but not limited to) age-associated dementia, immunologicalconditions, cancer, and physical and functional decline. Individualssuffering from or at risk of developing an aging-associated cognitiveimpairment that will benefit from treatment with the subject LTA4Hmodulatory agent(s), e.g., by the methods disclosed herein, includeindividuals that are about 50 years old or older, e.g., 60 years old orolder, 70 years old or older, 80 years old or older, 90 years old orolder, and 100 years old or older, i.e., between the age of about 50 and100, e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 yearsold, and are suffering from cognitive impairment associated with naturalaging process, e.g., mild cognitive impairment (M.C.I.); and individualsthat are about 50 years old or older, e.g., 60 years old or older, 70years old or older, 80 years old or older, 90 years old or older, andusually no older than 100 years old, i.e., between the ages of about 50and 90, e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 yearsold, that have not yet begun to show symptoms of cognitive impairment.Examples of cognitive impairments that are due to natural aging includethe following:

1. Mild Cognitive Impairment (M.C.I.)

Mild cognitive impairment is a modest disruption of cognition thatmanifests as problems with memory or other mental functions such asplanning, following instructions, or making decisions that have worsenedover time while overall mental function and daily activities are notimpaired. Thus, although significant neuronal death does not typicallyoccur, neurons in the aging brain are vulnerable to sub-lethalage-related alterations in structure, synaptic integrity, and molecularprocessing at the synapse, all of which impair cognitive function.Individuals suffering from or at risk of developing an aging-associatedcognitive impairment that will benefit from treatment with the subjectLTA4H modulatory agents, e.g., by the methods disclosed herein, alsoinclude individuals of any age that are suffering from a cognitiveimpairment due to an aging-associated disorder; and individuals of anyage that have been diagnosed with an aging-associated disorder that istypically accompanied by cognitive impairment, where the individual hasnot yet begun to present with symptoms of cognitive impairment. Examplesof such aging-associated disorders include the following:

2. Alzheimer's Disease

Alzheimer's disease is a progressive, inexorable loss of cognitivefunction associated with an excessive number of senile plaques in thecerebral cortex and subcortical gray matter, which also containsb-amyloid and neurofibrillary tangles consisting of tau protein. Thecommon form affects persons >60 yr old, and its incidence increases asage advances. It accounts for more than 65% of the dementias in theelderly.

The cause of Alzheimer's disease is not known. The disease runs infamilies in about 15 to 20% of cases. The remaining, so-called sporadiccases have some genetic determinants. The disease has an autosomaldominant genetic pattern in most early-onset and some late-onset casesbut a variable late-life penetrance. Environmental factors are the focusof active investigation.

In the course of the disease, synapses, and ultimately neurons are lostwithin the cerebral cortex, hippocampus, and subcortical structures(including selective cell loss in the nucleus basalis of Meynert), locuscoeruleus, and nucleus raphae dorsalis. Cerebral glucose use andperfusion is reduced in some areas of the brain (parietal lobe andtemporal cortices in early-stage disease, prefrontal cortex inlate-stage disease). Neuritic or senile plaques (composed of neurites,astrocytes, and glial cells around an amyloid core) and neurofibrillarytangles (composed of paired helical filaments) play a role in thepathogenesis of Alzheimer's disease. Senile plaques and neurofibrillarytangles occur with normal aging, but they are much more prevalent inpersons with Alzheimer's disease.

3. Parkinson's Disease

Parkinson's Disease (PD) is an idiopathic, slowly progressive,degenerative CNS disorder characterized by slow and decreased movement(bradykinesia), muscular rigidity, resting tremor (dystonia), musclefreezing, and postural instability. Originally considered primarily amotor disorder, PD is now recognized to also cause depression andemotional changes. PD also can affect cognition, behavior, sleep,autonomic function, and sensory function. The most common cognitiveimpairments include an impairment in attention and concentration,working memory, executive function, producing language, and visuospatialfunction. A characteristic of PD is symptoms related to reduced motorfunction usually precede those related to cognitive impairment, whichaids in diagnosis of the disease.

In primary Parkinson's disease, the pigmented neurons of the substantianigra, locus coeruleus, and other brain stem dopaminergic cell groupsdegenerate. The cause is not known. The loss of substantia nigraneurons, which project to the caudate nucleus and putamen, results indepletion of the neurotransmitter dopamine in these areas. Onset isgenerally after age 40, with increasing incidence in older age groups.

Parkinson's disease is newly diagnosed in about 60,000 Americans eachyear and currently affects approximately one million Americans. Eventhough PD is not fatal in itself, its complications are the fourteenthleading cause of death in the United States. At present, PD cannot becured, and treatment is generally prescribed to control symptoms, withsurgery prescribed in later, severe cases.

Treatment options for PD include administration of pharmaceuticals tohelp manage motor deficits. These options increase or substitute for theneurotransmitter, dopamine, of which PD patients have low brainconcentrations. Such medications include: carbidopa/levodopa (whichcreate more dopamine in the brain); apomorphine, pramipexolole,ropinirole, and rotingotine (dopamine agonists); selegiline andrasagiline (MAO-B inhibitors which prevent breakdown of dopamine);entacapone and tolcapone (Catechol-O-methyltransferase [COMT] inhibitorswhich make more levodopa available in the brain); benztropine andtrihexyphenidyl (anticholinergics); and amantadine (controls tremor andstiffness). Exercise/physical therapy is also commonly prescribed tohelp maintain physical and mental function.

Current treatment options, however treat the symptoms of PD, are notcurative, and fail to prevent disease progression. Additionally, currentmedications tend to lose efficacy in late stage PD. The most prescribeddrug, levodopa, commonly results in adverse effects within 5 to 10 yearsafter commencing the medication. These adverse effects can be severe andcan result in motor fluctuations and unpredictable swings in motorcontrol between doses as well as jerking/twitching (dyskinesia) whichare difficult to manage and are even as disabling as PD's own symptoms.Thus, there remains a need for new therapies with new mechanisms ofaction which can either be administrated along or in combination withcurrent PD medications.

4. Parkinsonism

Secondary parkinsonism (also referred to as atypical Parkinson's diseaseor Parkinson's plus) results from loss of or interference with theaction of dopamine in the basal ganglia due to other idiopathicdegenerative diseases, drugs, or exogenous toxins. The most common causeof secondary parkinsonism is ingestion of antipsychotic drugs orreserpine, which produce parkinsonism by blocking dopamine receptors.Less common causes include carbon monoxide or manganese poisoning,hydrocephalus, structural lesions (tumors, infarcts affecting themidbrain or basal ganglia), subdural hematoma, and degenerativedisorders, including nigrostriatal degeneration. Certain disorders likeProgressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA),Corticobasal degeneration (CBD) and Dementia with Lewy Bodies (DLB) canexhibit Parkinsonism symptoms before the cardinal symptoms necessary tothe specific diagnosis can be made, and thus may be labeled as“Parkinsonism.”

5. Frontotemporal Dementia

Frontotemporal dementia (FTD) is a condition resulting from theprogressive deterioration of the frontal lobe of the brain. Over time,the degeneration may advance to the temporal lobe. Second only toAlzheimer's disease (AD) in prevalence, FTD accounts for 20% ofpre-senile dementia cases. Symptoms are classified into three groupsbased on the functions of the frontal and temporal lobes affected:

Behavioral variant FTD (bvFTD), with symptoms include lethargy andaspontaneity on the one hand, and disinhibition on the other;progressive nonfluent aphasia (PNFA), in which a breakdown in speechfluency due to articulation difficulty, phonological and/or syntacticerrors is observed but word comprehension is preserved; and semanticdementia (SD), in which patients remain fluent with normal phonology andsyntax but have increasing difficulty with naming and wordcomprehension. Other cognitive symptoms common to all FTD patientsinclude an impairment in executive function and ability to focus. Othercognitive abilities, including perception, spatial skills, memory andpraxis typically remain intact. FTD can be diagnosed by observation ofreveal frontal lobe and/or anterior temporal lobe atrophy in structuralMRI scans.

A number of forms of FTD exist, any of which may be treated or preventedusing the subject methods and compositions. For example, one form offrontotemporal dementia is Semantic Dementia (SD). SD is characterizedby a loss of semantic memory in both the verbal and non-verbal domains.SD patients often present with the complaint of word-findingdifficulties. Clinical signs include fluent aphasia, anomia, impairedcomprehension of word meaning, and associative visual agnosia (theinability to match semantically related pictures or objects). As thedisease progresses, behavioral and personality changes are often seensimilar to those seen in frontotemporal dementia although cases havebeen described of ‘pure’ semantic dementia with few late behavioralsymptoms. Structural MRI imaging shows a characteristic pattern ofatrophy in the temporal lobes (predominantly on the left), with inferiorgreater than superior involvement and anterior temporal lobe atrophygreater than posterior.

As another example, another form of frontotemporal dementia is Pick'sdisease (PiD, also PcD). A defining characteristic of the disease isbuild-up of tau proteins in neurons, accumulating into silver-staining,spherical aggregations known as “Pick bodies.” Symptoms include loss ofspeech (aphasia) and dementia. Patients with orbitofrontal dysfunctioncan become aggressive and socially inappropriate. They may steal ordemonstrate obsessive or repetitive stereotyped behaviors. Patients withdorsomedial or dorsolateral frontal dysfunction may demonstrate a lackof concern, apathy, or decreased spontaneity. Patients can demonstratean absence of self-monitoring, abnormal self-awareness, and an inabilityto appreciate meaning. Patients with gray matter loss in the bilateralposterolateral orbitofrontal cortex and right anterior insula maydemonstrate changes in eating behaviors, such as a pathologic sweettooth. Patients with more focal gray matter loss in the anterolateralorbitofrontal cortex may develop hyperphagia. While some of the symptomscan initially be alleviated, the disease progresses, and patients oftendie within two to ten years.

6. Huntington's Disease

Huntington's disease (HD) is a hereditary progressive neurodegenerativedisorder characterized by the development of emotional, behavioral, andpsychiatric abnormalities; loss of intellectual or cognitivefunctioning; and movement abnormalities (motor disturbances). Theclassic signs of HD include the development of chorea—involuntary,rapid, irregular, jerky movements that may affect the face, arms, legs,or trunk—as well as cognitive decline including the gradual loss ofthought processing and acquired intellectual abilities. There may beimpairment of memory, abstract thinking, and judgment; improperperceptions of time, place, or identity (disorientation); increasedagitation; and personality changes (personality disintegration).Although symptoms typically become evident during the fourth or fifthdecades of life, the age at onset is variable and ranges from earlychildhood to late adulthood (e.g., 70s or 80s).

HD is transmitted within families as an autosomal dominant trait. Thedisorder occurs as the result of abnormally long sequences or “repeats”of coded instructions within a gene on chromosome 4 (4p16.3). Theprogressive loss of nervous system function associated with HD resultsfrom loss of neurons in certain areas of the brain, including the basalganglia and cerebral cortex.

7. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariablyfatal, neurological disease that attacks motor neurons. Muscularweakness and atrophy and signs of anterior horn cell dysfunction areinitially noted most often in the hands and less often in the feet. Thesite of onset is random, and progression is asymmetric. Cramps arecommon and may precede weakness. Rarely, a patient survives 30 years;50% die within 3 years of onset, 20% live 5 years, and 10% live 10years.

Diagnostic features include onset during middle or late adult life andprogressive, generalized motor involvement without sensoryabnormalities. Nerve conduction velocities are normal until late in thedisease. Recent studies have documented the presentation of cognitiveimpairments as well, particularly a reduction in immediate verbalmemory, visual memory, language, and executive function.

A decrease in cell body area, number of synapses and total synapticlength has been reported in even normal-appearing neurons of the ALSpatients. It has been suggested that when the plasticity of the activezone reaches its limit, a continuing loss of synapses can lead tofunctional impairment. Promoting the formation or new synapses orpreventing synapse loss may maintain neuron function in these patients.

8. Multiple Sclerosis

Multiple Sclerosis (MS) is characterized by various symptoms and signsof CNS dysfunction, with remissions and recurring exacerbations. Themost common presenting symptoms are paresthesias in one or moreextremities, in the trunk, or on one side of the face; weakness orclumsiness of a leg or hand; or visual disturbances, e.g., partialblindness and pain in one eye (retrobulbar optic neuritis), dimness ofvision, or scotomas. Common cognitive impairments include impairments inmemory (acquiring, retaining, and retrieving new information), attentionand concentration (particularly divided attention), informationprocessing, executive functions, visuospatial functions, and verbalfluency. Common early symptoms are ocular palsy resulting in doublevision (diplopia), transient weakness of one or more extremities, slightstiffness or unusual fatigability of a limb, minor gait disturbances,difficulty with bladder control, vertigo, and mild emotionaldisturbances; all indicate scattered CNS involvement and often occurmonths or years before the disease is recognized. Excess heat mayaccentuate symptoms and signs.

The course is highly varied, unpredictable, and, in most patients,remittent. At first, months or years of remission may separate episodes,especially when the disease begins with retrobulbar optic neuritis.However, some patients have frequent attacks and are rapidlyincapacitated; for a few the course can be rapidly progressive.

9. Glaucoma

Glaucoma is a common neurodegenerative disease that affects retinalganglion cells (RGCs). Evidence supports the existence ofcompartmentalized degeneration programs in synapses and dendrites,including in RGCs. Recent evidence also indicates a correlation betweencognitive impairment in older adults and glaucoma (Yochim B P, et al.Prevalence of cognitive impairment, depression, and anxiety symptomsamong older adults with glaucoma. J Glaucoma. 2012; 21(4):250-254).

10. Myotonic Dystrophy

Myotonic dystrophy (DM) is an autosomal dominant multisystem disordercharacterized by dystrophic muscle weakness and myotonia. The moleculardefect is an expanded trinucleotide (CTG) repeat in the 3′ untranslatedregion of the myotonin protein kinase gene on chromosome 19q. Symptomscan occur at any age, and the range of clinical severity is broad.Myotonia is prominent in the hand muscles, and ptosis is common even inmild cases. In severe cases, marked peripheral muscular weakness occurs,often with cataracts, premature balding, hatchet facies, cardiacarrhythmias, testicular atrophy, and endocrine abnormalities (e.g.,diabetes mellitus). Mental retardation is common in severe congenitalforms, while an aging-related decline of frontal and temporal cognitivefunctions, particularly language and executive functions, is observed inmilder adult forms of the disorder. Severely affected persons die bytheir early 50s.

11. Dementia

Dementia describes a class of disorders having symptoms affectingthinking and social abilities severely enough to interfere with dailyfunctioning. Other instances of dementia in addition to the dementiaobserved in later stages of the aging-associated disorders discussedabove include vascular dementia, and dementia with Lewy bodies,described below.

In vascular dementia, or “multi-infarct dementia”, cognitive impairmentis caused by problems in supply of blood to the brain, typically by aseries of minor strokes, or sometimes, one large stroke preceded orfollowed by other smaller strokes. Vascular lesions can be the result ofdiffuse cerebrovascular disease, such as small vessel disease, or focallesions, or both. Patients suffering from vascular dementia present withcognitive impairment, acutely or subacutely, after an acutecerebrovascular event, after which progressive cognitive decline isobserved. Cognitive impairments are similar to those observed inAlzheimer's disease, including impairments in language, memory, complexvisual processing, or executive function, although the related changesin the brain are not due to AD pathology but to chronic reduced bloodflow in the brain, eventually resulting in dementia. Single photonemission computed tomography (SPECT) and positron emission tomography(PET) neuroimaging may be used to confirm a diagnosis of multi-infarctdementia in conjunction with evaluations involving mental statusexamination.

Dementia with Lewy bodies (DLB, also known under a variety of othernames including Lewy body dementia, diffuse Lewy body disease, corticalLewy body disease, and senile dementia of Lewy type) is a type ofdementia characterized anatomically by the presence of Lewy bodies(clumps of alpha-synuclein and ubiquitin protein) in neurons, detectablein post mortem brain histology. Its primary feature is cognitivedecline, particularly of executive functioning. Alertness and short-termmemory will rise and fall.

Persistent or recurring visual hallucinations with vivid and detailedpictures are often an early diagnostic symptom. DLB it is often confusedin its early stages with Alzheimer's disease and/or vascular dementia,although, where Alzheimer's disease usually begins quite gradually, DLBoften has a rapid or acute onset. DLB symptoms also include motorsymptoms similar to those of Parkinson's. DLB is distinguished from thedementia that sometimes occurs in Parkinson's disease by the time framein which dementia symptoms appear relative to Parkinson symptoms.Parkinson's disease with dementia (POD) would be the diagnosis whendementia onset is more than a year after the onset of Parkinson's. DLBis diagnosed when cognitive symptoms begin at the same time or within ayear of Parkinson symptoms.

12. Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a brain disorder that causesserious and progressive problems with control of gait and balance, alongwith complex eye movement and thinking problems. One of the classicsigns of the disease is an inability to aim the eyes properly, whichoccurs because of lesions in the area of the brain that coordinates eyemovements. Some individuals describe this effect as a blurring. Affectedindividuals often show alterations of mood and behavior, includingdepression and apathy as well as progressive mild dementia. Thedisorder's long name indicates that the disease begins slowly andcontinues to get worse (progressive), and causes weakness (palsy) bydamaging certain parts of the brain above pea-sized structures callednuclei that control eye movements (supranuclear). PSP was firstdescribed as a distinct disorder in 1964, when three scientistspublished a paper that distinguished the condition from Parkinson'sdisease. It is sometimes referred to as Steele-Richardson-Olszewskisyndrome, reflecting the combined names of the scientists who definedthe disorder. Although PSP gets progressively worse, no one dies fromPSP itself.

13. Ataxia

People with ataxia have problems with coordination because parts of thenervous system that control movement and balance are affected. Ataxiamay affect the fingers, hands, arms, legs, body, speech, and eyemovements. The word ataxia is often used to describe a symptom ofincoordination which can be associated with infections, injuries, otherdiseases, or degenerative changes in the central nervous system. Ataxiais also used to denote a group of specific degenerative diseases of thenervous system called the hereditary and sporadic ataxias which are theNational Ataxia Foundation's primary emphases.

14. Multiple-System Atrophy

Multiple-system atrophy (MSA) is a degenerative neurological disorder.MSA is associated with the degeneration of nerve cells in specific areasof the brain. This cell degeneration causes problems with movement,balance, and other autonomic functions of the body such as bladdercontrol or blood-pressure regulation.

The cause of MSA is unknown and no specific risk factors have beenidentified. Around 55% of cases occur in men, with typical age of onsetin the late 50s to early 60s. MSA often presents with some of the samesymptoms as Parkinson's disease. However, MSA patients generally showminimal if any response to the dopamine medications used forParkinson's.

15. Frailty

Frailty Syndrome (“Frailty”) is a geriatric syndrome characterized byfunctional and physical decline including decreased mobility, muscleweakness, physical slowness, poor endurance, low physical activity,malnourishment, and involuntary weight loss. Such decline is oftenaccompanied and a consequence of diseases such as cognitive dysfunctionand cancer. However, Frailty can occur even without disease. Individualssuffering from Frailty have an increased risk of negative prognosis fromfractures, accidental falls, disability, comorbidity, and prematuremortality. (C. Buigues, et al. Effect of a Prebiotic Formulation onFrailty Syndrome: A Randomized, Double-Blind Clinical Trial, Int. J.Mol. Sci. 2016, 17, 932). Additionally, individuals suffering fromFrailty have an increased incidence of higher health care expenditure.(Id.)

Common symptoms of Frailty can be determined by certain types of tests.For example, unintentional weight loss involves a loss of at least 10lbs. or greater than 5% of body weight in the preceding year; muscleweakness can be determined by reduced grip strength in the lowest 20% atbaseline (adjusted for gender and BMI); physical slowness can be basedon the time needed to walk a distance of 15 feet; poor endurance can bedetermined by the individual's self-reporting of exhaustion; and lowphysical activity can be measured using a standardized questionnaire.(Z. Palace et al., The Frailty Syndrome, Today's Geriatric Medicine7(1), at 18 (2014)).

In some embodiments, the subject methods and compositions find use inslowing the progression of aging-associated cognitive, motor,neuroinflammatory, neurodegenerative, or other age-related impairment orcondition. In other words, cognitive, motor, neuroinflammatory,neurodegenerative, or other abilities or conditions in the individualwill decline more slowly following treatment by the disclosed methodsthan prior to or in the absence of treatment by the disclosed methods.In some such instances, the subject methods of treatment includemeasuring the progression of cognitive, motor, neuroinflammation, orother age-related ability or symptom decline after treatment, anddetermining that the progression of decline is reduced. In some suchinstances, the determination is made by comparing to a reference, e.g.,the rate of decline in the individual prior to treatment, e.g., asdetermined by measuring cognitive, motor, neuroinflammatory, or otherage-related abilities or conditions prior at two or more time pointsprior to administration of the subject blood product.

The subject methods and compositions also find use in stabilizing thecognitive, motor, neuroinflammatory, or other abilities or conditions ofan individual, e.g., an individual suffering from aging-associatedcognitive decline or an individual at risk of suffering fromaging-associated cognitive decline. For example, the individual maydemonstrate some aging-associated cognitive impairment, and progressionof cognitive impairment observed prior to treatment with the disclosedmethods will be halted following treatment by the disclosed methods. Asanother example, the individual may be at risk for developing anaging-associated cognitive decline (e.g., the individual may be aged 50years old or older or may have been diagnosed with an aging-associateddisorder), and the cognitive abilities of the individual aresubstantially unchanged, i.e., no cognitive decline can be detected,following treatment by the disclosed methods as compared to prior totreatment with the disclosed methods.

The subject methods and compositions also find use in reducingcognitive, motor, neuroinflammatory, or other age-related impairment inan individual suffering from an aging-associated impairment. In otherwords, the affected ability is improved in the individual followingtreatment by the subject methods. For example, the cognitive or motorability in the individual is increased, e.g., by 2-fold or more, 5-foldor more, 10-fold or more, 15-fold or more, 20-fold or more, 30-fold ormore, or 40-fold or more, including 50-fold or more, 60-fold or more,70-fold or more, 80-fold or more, 90-fold or more, or 100-old or more,following treatment by the subject methods relative to the cognitive ormotor ability that is observed in the individual prior to treatment bythe subject methods.

In some instances, treatment by the subject methods and compositionsrestores the cognitive, motor, or other ability in the individualsuffering from aging-associated cognitive or motor decline, e.g., totheir level when the individual was about 40 years old or less. In otherwords, cognitive or motor impairment is abrogated.

16. Neuromvelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorder (NMOSD), also known as Devicdisease, is a rare, inflammatory disease of the central nervous system.It is characterized by optic neuritis (optic nerve inflammation) andmyelitis (spinal cord inflammation). Typically, patients experiencereoccurring bouts of inflammation separated by periods of remission. Thedisease is thought to be caused by auto-antibodies that often targetmyelin oligodendrocyte glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG),which leads to demyelination and axonal damage in the optic nerve andspinal cord.

17. Post-Operative Cognitive Dysfunction

Post-operative cognitive decline occurs following anesthesia and asurgical procedure. It is common in patients older than 60 and isdiagnosed by pre- and post-surgery cognitive testing. Patients typicallypresent with memory impairment, delirium, and impairment in performanceon intellectual tasks.

18. Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative braindisorder most commonly found in athletes, veterans, or others with ahistory of repeated head trauma. It is one of many tauopathies that ischaracterized by the overabundance of Tau protein in the brain ofpatients that leads to neuron loss. Symptoms include memory loss,changes in mood or personality, confusion, impaired judgement, impulsecontrol, aggression, and depression.

19. Traumatic Brain Injury

Traumatic brain injury (TBI) is caused by a violent hit to the head orbody. It can also be caused by an object penetrating brain tissue duringan injury. It results in bleeding, torn tissue, and physical damage tobrain cells and cell death. The physical symptoms are varied, butinclude loss of consciousness, headaches, nausea, extreme fatigue,impaired speech, trouble sleeping, dizziness, blurred vision,sensitivity to light or sound, memory loss, and concentration problems.

F. Methods of Diagnosing and Monitoring for Improvement

In some instances, among the variety of methods to diagnose and monitordisease progression and improvement in cognitive disease, motorimpairment, neuroinflammatory, or neurodegenerative disease thefollowing types of assessments are used alone or in combination withsubjects suffering from neurodegenerative disease, as desired. Thefollowing types of methods are presented as examples and are not limitedto the recited methods. Any convenient methods to monitor disease may beused in practicing the invention, as desired. Those methods are alsocontemplated by the methods of the invention.

1. General Cognition

Embodiments of the methods of the invention further comprise methods ofmonitoring the effect of a medication or treatment on a subject fortreating cognitive impairment and/or age-related dementia, the methodcomprising comparing cognitive function before and after treatment.Those having ordinary skill in the art recognize that there arewell-known methods of evaluating cognitive function. For example, andnot by way of limitation, the method may comprise evaluation ofcognitive function based on medical history, family history, physicaland neurological examinations by clinicians who specialize dementia andcognitive function, laboratory tests, and neuropsychological assessment.Additional embodiments which are contemplated by the invention include:the assessment of consciousness, such as using the Glasgow Coma Scale(EMV); mental status examination, including the abbreviated mental testscore (AMTS) or mini-mental state examination (MMSE) (Folstein et al.,J. Psychiatr. Res 1975; 12:1289-198); global assessment of higherfunctions; estimation of intracranial pressure such as by fundoscopy. Inone embodiment, monitoring the effect on cognitive impairment and/orage-related dementia includes a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or12-point improvement using the Alzheimer's Disease AssessmentScale-Cognitive Subscale (ADAS-COG).

In one embodiment, examinations of the peripheral nervous system may beused to evaluate cognitive function, including any one of thefollowings: sense of smell, visual fields and acuity, eye movements andpupils (sympathetic and parasympathetic), sensory function of face,strength of facial and shoulder girdle muscles, hearing, taste,pharyngeal movement and reflex, tongue movements, which can be testedindividually (e.g. the visual acuity can be tested by a Snellen chart; areflex hammer used testing reflexes including masseter, biceps andtriceps tendon, knee tendon, ankle jerk and plantar (i.e. Babinskisign); Muscle strength often on the MRC scale 1 to 5; Muscle tone andsigns of rigidity.

2. Parkinson's Disease

Embodiments of the methods of the invention further comprise methods ofmonitoring the effect of a medication or treatment on a subject fortreating motor impairment, the method comprising comparing motorfunction before and after treatment. Those having ordinary skill in theart recognize that there are well-known methods of evaluating motorfunction. For example, and not by way of limitation, the method maycomprise evaluation of motor function based on medical history, familyhistory, physical and neurological examinations by clinicians whospecialize neurodegeneration and motor impairment, laboratory tests, andneurodegenerative assessment. Additional embodiments which arecontemplated by the invention include employment of the rating scalesdiscussed below.

Several rating scales have been utilized for evaluating the progressionof PD. The most widely-used scales include the Unified Parkinson'sDisease Rating Scale (UPDRS, which was introduced in 1987) (J. RehabilRes. Dev., 2012 49(8): 1269-76), and the Hoehn and Yahr scale(Neurology, 1967 17(5): 427-42). Additional scales include the MovementDisorder Society (MDS)'s updated UPDRS scale (MDS-UPDRS) as well as theSchwab and England Activities of Daily Living (ADL) Scale.

The UPDRS scale evaluates 31 items that contributed to three subscales:(1) mentation, behavior, and mood; (2) activities of daily living; and(3) motor examination. The Hoehn and Yahr scale classifies PD into fivestages with discreet substages: 0—no signs of disease; 1—symptoms on oneside only; 1.5—symptoms on one side but also involving neck and spine;2—symptoms on both sides with no balance impairment; 2.5—mild symptomson both sides, with recovery when the ‘pull’ test is given; 3—balanceimpairment with mild to moderate disease; 4—severe disability, butability to walk or stand unassisted; and 5—need a wheelchair orbedridden without assistance. The Schwab and England scale classifies PDinto several percentages (from 100%—complete independent to 10%—totaldependent).

General motor function can be evaluated using widely-used scalesincluding the General Motor Function Scale (GMF). This tests threecomponents: dependence, pain, and insecurity. (Aberg A. C., et al.(2003) Disabil. Rehabil. 2003 May 6; 25(9):462-72.). Motor function canalso be assessed using home-monitoring or wearable sensors. For example:gait (speed of locomotion, variability, leg rigidity) can be sensed withan accelerometer; posture (trunk inclination) by a gyroscope; legmovement by an accelerometer; hand movement by an accelerometer andgyroscope; tremor (amplitude, frequency, duration, asymmetry) by anaccelerometer; falling by an accelerometer; gait freezing by anaccelerometer; dyskinesia by an accelerometer, gyroscope, and inertialsensors; bradykinesia (duration and frequency) by an accelerometer plusgyroscope, and aphasia (pitch) using a microphone. (Pastorino M, et al.,Journal of Physics: Conference Series 450 (2013) 012055).

3. Multiple Sclerosis

In addition to monitoring improvement for symptoms associated withcognition, the progression or improvement of neurodegenerationassociated with multiple sclerosis (MS) can be monitored usingtechniques well-known to those having ordinary skill in the art. By wayof example, and not limitation, monitoring can be performed throughtechniques such as: cerebrospinal fluid (CSF) monitoring; magneticresonance imaging (MRI) to detect lesions and development ofdemyelinating plaques; evoked potential studies; and gait monitoring.

CSF analysis may be performed, for example, through lumbar puncture toobtain pressure, appearance, and CSF content. Normal values typicallyrange as follows: pressure (70-180 mm H20); appearance is clear andcolorless; total protein (15-60 mg/100 mL); IgG is 3-12% of the totalprotein; glucose is 50-80 mg/100 mL; cell count is 0-5 white blood cellsand no red blood cells; chloride (110-125 mEq/L). Abnormal results mayindicate the presence or progression of MS.

MRI is another technique that may be performed to monitor diseaseprogression and improvement. Typical criteria for monitoring MS with MRIinclude the appearance of patchy areas of abnormal white matter incerebral hemisphere and in paraventricular areas, lesions present in thecerebellum and/or brain stem as well as in the cervical or thoracicregions of the spinal cord.

Evoked potentials may be used to monitor the progression and improvementof MS in subjects. Evoked potentials measure slowing of electricalimpulses such as in Visual Evoked Response (VER), Brain Stem AuditoryEvoked Responses (BAER), and Somatosensory Evoked Responses (SSER).Abnormal responses help to indicate that there is a decrease in thespeed of conduction in central sensory pathways.

Gait monitoring can also be used to monitor disease progression andimprovement in MS subjects. MS is often accompanied by an impairment inmobility and an abnormal gait due in part to fatigue. Monitoring may beperformed, for example, with the use of mobile monitoring devices wornby subjects. (Moon, Y., et al., Monitoring gait in multiple sclerosiswith novel wearable motion sensors, PLOS One, 12(2):e0171346 (2017)).

4. Huntington's Disease

In addition to monitoring improvement for symptoms associated withcognition, the progression or improvement of neurodegenerationassociated with Huntington's Disease (HD) can be monitored usingtechniques well-known to those having ordinary skill in the art. By wayof example, and not limitation, monitoring can be performed throughtechniques such as: motor function; behavior; functional assessment; andimaging.

Examples of motor function that may be monitored as an indication ofdisease progression or improvement include chorea and dystonia,rigidity, bradykinesia, oculomotor dysfunction, and gait/balancechanges. Techniques for performing the monitoring of these metrics arewell-known to those having ordinary skill in the art. (See Tang C, etal., Monitoring Huntington's disease progression through preclinical andearly stages, Neurodegener Dis Manag 2(4):421-35 (2012)).

The psychiatric effects of HD present opportunities to monitor diseaseprogression and improvement. For example, psychiatric diagnoses may beperformed in order to determine whether the subject suffers fromdepression, irritability, agitation, anxiety, apathy and psychosis withparanoia. (Id.)

Functional assessment may also be employed to monitor diseaseprogression or improvement. Total functional score techniques have beenreported (Id.), and often declines by one point per year in some HDgroups.

MRI or PET may be employed also to monitor disease progression orimprovement. For example, there is a loss of striatal projection neuronsin HD and change in number of these neurons may be monitored insubjects. Techniques to determine neuronal change in HD subjects includeimaging Dopamine D2 receptor binding. (Id.)

5. ALS

In addition to monitoring improvement for symptoms associated withcognition, the progression or improvement of neurodegenerationassociated with Amyotrophic Lateral Sclerosis (ALS) can be monitoredusing techniques well-known to those having ordinary skill in the art.By way of example, and not limitation, monitoring can be performedthrough techniques such as: functional assessment; determining musclestrength; measuring respiratory function; measuring lower motor neuron(LMN) loss; and measuring upper motor neuron (UMN) dysfunction.

Functional assessment can be performed using a functional scalewell-known to those having ordinary skill in the art, such as the ALSFunctional Rating Scale (ALSFRS-R), which evaluates symptoms related tobulbar, limb, and respiratory function. The rate of change is useful inpredicting survival as well as disease progression or improvement.Another measure includes the Combined Assessment of Function andSurvival (CAFS), ranking subjects' clinical outcomes by combiningsurvival time with change in ALSFRS-R. (Simon N G, et al., QuantifyingDisease Progression in Amyotrophic Lateral Sclerosis, Ann Neurol76:643-57 (2014)).

Muscle strength may be tested and quantified through use of compositeManual Muscle Testing (MMT) scoring. This entails averaging measuresacquired from several muscle groups using the Medical Research Council(MRC) muscle strength grading scale. (Id.) Hand-held dynamometry (HHD)may also be used, among other techniques. (Id.)

Respiratory function can be performed using portable spirometry units,used to obtain Forced Vital Capacity (FVC) at baseline to predict theprogression or improvement of the disease. Additionally, maximalinspiratory pressure, sniff nasal inspiratory pressure (SNIP), andsupping FVC may be determined and used to monitor diseaseprogression/improvement. (Id.)

Loss in lower motor neurons is another metric which can be utilized tomonitor disease progression or improvement in ALS. TheNeurophysiological Index may be determined by measuring compound muscleaction potentials (CMAPs) on motor nerve conduction studies, of whichparameters include CMAP amplitude and F-wave frequency. (Id. and deCarvalho M, et al., Nerve conduction studies in amyotrophic lateralsclerosis. Muscle Nerve 23:344-352, (2000)). Lower motor neuron unitnumbers (MUNE) may be estimated as well. In MUNE, the number of residualmotor axons supplying a muscle through estimation of the contribution ofindividual motor units to the maximal CMAP response is estimated andused to determine disease progression or improvement. (Simon N G, etal., supra). Additional techniques for determining loss of LMN includetesting nerve excitability, electrical impedance myography, and usingmuscle ultrasound to detect changes in thickness in muscles. (Id.)

Dysfunction of upper motor neurons is another metric which can beutilized to monitor disease progression or improvement in ALS.Techniques for determining dysfunction include performing MRI or PETscans on the brain and spinal cord, transcranial magnetic stimulation;and determining levels of biomarkers in the cerebrospinal fluid (CSF).

6. Glaucoma

In addition to monitoring improvement for symptoms associated withcognition, the progression or improvement of neurodegenerationassociated with glaucoma can be monitored using techniques well-known tothose having ordinary skill in the art. By way of example, and notlimitation, monitoring can be performed through techniques such as:determining intraocular pressure; assessment of the optic disc or opticnerve head for damage; visual field testing for peripheral vision loss;and imaging of the optic disc and retina for topographic analysis.

7. Progressive Supranuclear Palsy (PSP)

In addition to monitoring improvement for symptoms associated withcognition, the progression or improvement of neurodegenerationassociated with Progressive Supranuclear Palsy (PSP) can be monitoredusing techniques well-known to those having ordinary skill in the art.By way of example, and not limitation, monitoring can be performedthrough techniques such as: functional assessment (activities of dailyliving, or ADL); motor assessment; determination of psychiatricsymptoms; and volumetric and functional magnetic resonance imaging(MRI).

The level of function of a subject in terms of independence, partialdependence upon others, or complete dependence can be useful fordetermining the progression or improvement in the disease. (See Duff, K,et al., Functional impairment in progressive supranuclear palsy,Neurology 80:380-84, (2013)). The Progressive Supranuclear Palsy RatingScale (PSPRS) is a rating scale that comprises twenty-eight metrics insix categories: daily activities (by history); behavior; bulbar, ocularmotor, limb motor and gait/midline. The result is a score ranging from0-100. Six items are graded 0-2 and twenty-two items graded 0-4 for apossible total of 100. The PSPRS scores are practical measures, androbust predictors of patient survival. They are also sensitive todisease progression and useful in monitoring disease progression orimprovement. (Golbe L I, et al., A clinical rating scale for progressivesupranuclear palsy, Brain 130:1552-65, (2007)).

The ADL section from the UPDRS (Unified Parkinson's Disease RatingScale) can also be used to quantify functional activity in subjects withPSP. (Duff K, et al., supra). Similarly, the Schwab & England ActivitiesDaily Living Score (SE-ADL) can be used for evaluating independence.(Id.) Additionally, the motor function sections of the UPDRS are usefulas a reliable measure for assessing disease progression in PSP patients.The motor section may contain, for example, 27 different measures forquantifying motor function in PSP patients. Examples of these includeresting tremor, rigidity, finger tapping, posture, and gait). Asubject's disease progression or improvement may also be assessed byperforming a baseline neuropsychological evaluation completed by trainedmedical personnel, the assessment using the Neuropsychiatric Inventory(NPI) to determine the frequency and severity of behavior abnormalities(e.g. delusions, hallucinations, agitation, depression, anxiety,euphoria, apathy, disinhibition, irritability, and aberrant motorbehavior). (Id.)

Functional MRI (fMRI) can be employed to monitor disease progression andimprovement as well. fMRI is a technique using MRI to measure changes inbrain activity in certain regions of the brain, usually based on bloodflow to those regions. Blood flow is considered to correlate with brainregion activation. Patients with neurodegenerative disorders like PSPcan be subjected to physical or mental tests before or during beingscanned in an MRI scanner. By way of example, and not limitation, testscan be a well-established force control paradigm where patients as askedto produce force with the hand most affected by PSP and maximumvoluntary contraction (MVC) is measured by fMRI immediately after thetest takes place. Burciu, R G, et al., Distinct patterns of brainactivity in progressive supranuclear palsy and Parkinson's disease, Mov.Disord. 30(9):1248-58 (2015)).

Volumetric MRI is a technique where MRI scanners determine volumedifferences in regional brain volume. This may be done, for example, bycontrasting different disorders, or by determining differences in volumeof a brain region in a patient over time. Volumetric MRI may be employedto determine disease progression or improvement in neurodegenerativedisorders like PSP. The technique is well-known to those having ordinaryskill in the art. (Messina D, et al., Patterns of brain atrophy inParkinson's disease, progressive supranuclear palsy and multiple systematrophy, Parkinsonism and Related Disorders, 17(3):172-76 (2011)).Examples of cerebral regions which may be measured include, but are notlimited to, intracranial volume, cerebral cortex, cerebellar cortex,thalamus, caudate, putamen, pallidum, hippocampus, amygdala, lateralventricles, third ventricle, fourth ventricle, and brain stem.

8. Neurogenesis

The invention also contemplates treating or improving neurogenesis in asubject with declining or impaired neurogenesis, which may manifestitself, for example, through reduced cognitive or motor function, orthrough association with neuroinflammation. An embodiment of theinvention includes administering, by way of example and not limitation,an LTA4H modulatory agent to the subject with reduced or impairedneurogenesis using a Pulsed Dosing treatment regimen.

An embodiment of the invention also contemplates determining the levelof neurogenesis before, during, and/or after administration of the LTA4Hmodulatory agent. Noninvasive techniques for evaluating neurogenesishave been reported. (Tamura Y. et al., J. Neurosci. (2016)36(31):8123-31). Positron emission tomography (PET) used with thetracer, [18F]FLT, in combinations with the BBB transporter inhibitorprobenecid, allows for accumulation of the tracer in neurogenic regionsof the brain. Such imaging allows for an evaluation of neurogenesis inpatients being treated for neurodegenerative disease.

9. Neuromyelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorder (NMOSD) can be diagnosed with ablood test to detect AQP4-IgG or MOG-IgG antibodies. Disease monitoringuses blood tests, cerebrospinal fluid tests, spinal taps, and magneticresonance imaging (MRI) or computed tomography (CT) scans.

G. Reagents, Devices, and Kits

Also provided are reagents, devices, and kits thereof for practicing oneor more of the above-described methods. The subject reagents, devices,and kits thereof may vary greatly. Reagents and devices of interestinclude those mentioned above with respect to the methods ofadministering the compositions described herein (e.g., LTA4H modulatoryagents) to the subject.

In addition to the above components, the subject kits will furtherinclude instructions for practicing the subject methods. Theseinstructions may be present in the subject kits in a variety of forms,one or more of which may be present in the kit. One form in which theseinstructions may be present is as printed information on a suitablemedium or substrate, e.g., a piece or pieces of paper on which theinformation is printed, in the packaging of the kit, in a packageinsert, etc. Yet another means would be a computer readable medium, e.g.diskette, CD, portable flash drive, etc., on which the information hasbeen recorded. Yet another means that may be present is a websiteaddress which may be used via the internet to access the information ata remote site. Any convenient means may be present in the kits.

H. Exercise

Exercise can be characterized by aerobic or anaerobic activity and caninvolve high calorie-burning activity and moderate calorie-burningactivity. Exercise may involve strength training (e.g. weight trainingor isometric exercise). Exercise may also involve, for example, running,bicycling, walking, dancing, marching, swimming, yoga, Tai Chi, balanceexercises, leg bends, jumping rope, surfing, rowing, rotating or flexingthe arms or legs, gardening, cleaning, active games such as bowling,aerobics, Pilates, and martial arts.

An exercise regimen may include performing a single exercise at acertain frequency, or a combination of exercises at a certain frequency.The frequency may be one, two, three, four, five, six, or seven timesper week. The frequency may vary from week-to-week. The exercise regimenmay be at the same level of intensity and/or frequency as the subjectpracticed before administration of the compositions of the invention.The exercise regimen may also be at a higher level of intensity and/orfrequency compared to the levels the subject practiced beforeadministration of the compositions of the invention. The exerciseregimen may have been suggested or prescribed by a health or fitnessprofessional, or the exercise regimen may have been initiated by thesubject himself or herself.

VII. EXPERIMENTAL EXAMPLES

The following examples are provided by way of illustration and not byway of limitation.

A. Experimental Procedures

1. Open Field/Novel Object Recognition

The open field test was used to evaluate general locomotor activity andexploratory behavior in a novel environment. It consisted of a squarearena (50 cm×50 cm). Mice were brought to the experimental room for atleast 30 min of acclimation to the experimental room conditions (dimlighting) prior to testing. Mice were placed in the center of the arenaand tracked using automated software (CleverSys or San DiegoInstruments) for 15 min. Total distance traveled, average velocity, andtime spent in the peripheral and center zones were analyzed.

2. Y-Maze

A large Y-maze test assessed short-term memory of the familiarity of aspecific context. Mice were brought to the experimental room for atleast 30 min of acclimation to the experimental room conditions (dimlighting) prior to testing. For the initial training trial, the mousewas placed at the end of one arm of a large Y-maze designated “startarm” (arm length: 15 inches). The third arm of the maze was blocked off,allowing the mouse to explore two of the three arms freely (“start arm”and “familiar arm”) for 5 min. Each arm contained spatial cues. Threehours later, the mouse was placed back into the maze in the “start arm,”and allowed to explore all three arms with the third arm unblocked(“novel arm”). Movements in and out of each arm were tracked usingautomated tracking software (CleverSys or San Diego Instruments).Testing was performed under dim lighting, and the apparatus was cleanedwith 70% ethanol between trials. The time spent and number of entiretiesinto the “novel arm” and “familiar arm” were analyzed, as well as totaldistance travelled and velocity as measures of general locomotoractivity.

3. Radial Arm Water Maze (RAWM)

The water maze (see, e.g. Alamed J, et al., Two-day radial-arm watermaze learning and memory tasks; robust resolution of amyloid-relatedmemory deficits in transgenic mice., Nat. Protoc., 1(4):1671-79 (2006)),was filled with water at least 24 hours prior to the test to equilibrateto 25° C. The water was dyed with white latex paint to make the animalsvisible for tracking and to allow for the use of a hidden platform.Eight distinct visual cues were placed at the end of each of eight armsof the RAWM inserts. On day 1 animals were subjected to 5 trials eachwith a visible platform and a 30-minute inter-trial interval. Animalshad 60 seconds to reach the platform. If they did not reach the platformin that time they were guided to it and allowed to remain for 15 secondsbefore being removed from the tank. The goal arm remained constant and adifferent start arm was randomly assigned for each of the 5 trials sothat mouse started in every arm once except for the two arms directlyacross from the platform. The goal arm was switched after every two miceand balanced between all treatment groups. After each trial the micewere placed in an empty cage with blue pads and allowed to dry off undera heat lamp before being placed back into their home cage. Testing daywas 48 hours after training, when animals were subjected to the sametest of 5 trials each and a 30-minute inter-trial interval, but with ahidden platform. Animals were scored for the number of errors (entryinto a non-goal arm) and for latency to reach the platform. All trialswere recorded using TopScan software (CleverSys, Inc., Reston, Va.).

4. Contextual Fear Conditioning (CFC)

Mice were brought into the testing room immediately before their trialto avoid exposure to sounds and scents from testing. Day 1: Fortraining, mice were placed in the chambers, bright house light and fanon, for 2 minutes. Then an auditory cue (2000 Hz, 70 dB, conditionedstimulus (CS)) was presented for 30 seconds. A 2 second foot shock (0.6mA; unconditioned stimulus (US)) was administered for the final 2seconds of the CS. This procedure was repeated once, each after a 2minute interval, and the mouse was removed from the chamber 30 secondsafter the second shock. The pans, chamber walls and grid floors werecleaned with 70% ethanol between trials. Day 2: Seventy-two hours afterthe training, the mouse was returned to the same chamber in which thetraining occurred (memory for context), and freezing behavior wasrecorded for 3 min. The mouse was returned to its home cage. The pans,chamber walls, and grid floors were cleaned with 70% ethanol betweentrials. Day 3: 24 hours after context testing, the mouse was returned tothe same chamber and freezing was recorded in a novel environment(altered context) and in response to the cue (memory for cue). The novelenvironment included different odors (Peppermint water), sounds, achamber divider, and different floor material. The mouse was placed inthe novel environment and freezing was recorded for 2 minutes. Theauditory cue (2000 Hz, 70 dB, CS) was then presented for 30 seconds, andfreezing was again recorded for 2 minutes. Mice were returned to theirhome cages, and the pans, chamber walls, and floors were cleaned withEthanol and with Peppermint water between trials.

5. Tissue Collection and Histology/Biochemistry

On the final day of dosing, mice were deeply anesthetized with Avertin(250 mg/kg IP). The mice are subjected to cardiac puncture and bloodsamples were collected using syringes pre-filled with EDTA or heparin.Blood was either subjected to calcimycin stimulation assay or separatedinto plasma by centrifugation. Plasma from each mouse was aliquoted andstored at −80° C.

Brains were collected following saline perfusion and separated bymid-sagittal slice with one-half drop fixed in freshly prepared 4% PFA.PFA was changed to 30% sucrose 24-48 hours later. A second change to 30%sucrose occurred 24 hours later. The second half was dissected intohippocampus and cortex and then snap frozen on dry ice.

Brain tissue was sectioned or lysed and analyzed for markers ofneurogenesis and aging by standard histological and biochemical methods,including qRT-PCR, Western blot, ELISA, and immunohistochemistry.

6. Experimental Reagents and Study Blinding

Recombinant human LTA4H (Bio-techne, 4008—SN) was buffer-exchanged intosterile PBS and dosed at 4.6 ug/150 uL by tail vein i.v. injection.SC-57461A (Cayman Chemical, 423169-68) stock solution was prepared at 10mg/mL in DMSO. Stock solution was diluted into sterile PBS immediatelyprior to p.o. dosing to a final concentration of 10% DMSO and 1 mg/mLSC-57461A. Mice were p.o. dosed at 5 mg/kg. CP-105,696 (Sigma, PZ0363),Pinostilbene hydrate (Sigma, SML0098), and Montelukast (Cayman Chemical,10008318) stock solutions were prepared at 30 mg/mL in EtOH/Solutol.Stock solutions were diluted into sterile PBS immediately prior to p.o.dosing to a final concentration of 10% EtOH and 3.3 mg/mL inhibitor.Administration to mice was performed p.o. at a dose of 10 mg/kg. Vehiclewas 10% EtOH/Solutol and was dosed p.o. at a volume of 150 uL.

SC-57461A (“SC’) is an LTA4H dual inhibitors, inhibiting both thehydrolase and peptidase activity of the enzyme. Pinostilbene hydrate(“PH”) is an inhibitor of the hydrolase activity of the enzyme.CP-105,696 (“CP”) is an LTB4 receptor antagonist, and Montelukast (“M”)is a cysteinyl receptor antagonist.

B. Example 1

The concentration of LTA4H protein or LTB4 lipid in young and old humanplasma was measured using a commercially-available LTA4H enzyme-linkedimmunosorbent assay (ELISA) (Quantikine ELISA, R&D Systems) or LTB4Parameter Kit (Enzo). Plasma samples were collected by plasmapheresis atGrifols and frozen within 30 min of collection. Per age group fiveindividual plasma samples were combined per pool and 7-9 pools weremeasured for the young and old plasma group representing 35-45individual donors.

FIG. 1A reports that quantification by ELISA shows a significantincrease in LTA4H with age between young and old human plasma samples.Young plasma from 20-year-old donors had an average concentration of 690ng/mL LTA4H while old plasma from 65-year-old donors had an averageconcentration of 1140 ng/mL LTA4H. All data shown are mean±s.e.m;****p<0.0001, Unpaired t test. n=8-9

FIG. 1B reports that quantification by ELISA shows an increase in LTB4levels with age between young and old human plasma samples. Young plasmafrom 20-year-old donors had an average concentration of 491 pg/mL LTB4while old plasma from 65-year-old donors had an average concentration of700 pg/mL LTB4. All data shown are mean±s.e.m; Unpaired t test. n=7.

C. Example 2

The concentration of mouse LTB4, the product of LTA4H enzyme hydrolysisactivity, was measured using commercially-available LTB4 parameter assaykits (R&D Systems and Enzo). Blood samples were collected by cardiacpuncture into pre-filled syringes with EDTA and injected into amicrocentrifuge tube. The plasma was separated by centrifugation at 1000g for 15 minutes at 4 C. Alternatively, blood was subjected to acalcimycin stimulation assay to increase the production of LTB4 prior toplasma collection. All plasma was stored at −80 C until measurement ofLTB4 levels. LTB4 levels were measured from the plasma from 4-15individual young (3 month, 3M) or aged (22.5 month, 22.5M) wild-typemice (WT; C57BL/6).

FIG. 2A reports that quantification by ELISA shows a significantincrease in LTB4 levels with age between young and old mouse plasmasamples. Young plasma from 3-month-old mice had an average concentrationof 1000 pg/mL LTB4 while old plasma from 22.5-month-old mice had anaverage concentration of 1191 pg/mL LTB4. All data shown are mean±s.e.m;**p<0.01, Unpaired t test. n=11-15.

FIG. 2B reports that quantification by ELISA shows a significantincrease in LTB4 levels with age between young and old mouse plasmasamples from both unstimulated and calcimycin stimulated blood. Youngplasma from 3-month-old mice had an average concentration of 708 pg/mLLTB4 while old plasma from 22.5-month-old mice had an averageconcentration of 946 pg/mL LTB4. Stimulated young plasma from3-month-old mice had an average concentration of 1739 pg/mL LTB4 whilestimulated old plasma from 22.5-month-old mice had an averageconcentration of 3686 pg/mL LTB4. All data shown are mean±s.e.m;*p<0.05, **p<0.01, ****p<0.0001. Unpaired t test. n=4-8.

D. Example 3

Young, 8-week old wild-type (WT; C57BL/6) mice were homogenized betweengroups by body weight. Following group determination, mice were injectedintraperitoneally (IP) with BrdU (5-bromo-2′-deoxyuridine) formulated inPBS (phosphate buffered saline) at a final concentration of 10 mg/mLdosed at 150 mg/kg for 5 days. Immediately following the BrdU dosing,group 1 was injected intravenously (IV) with PBS control and group 2with recombinant human LTA4H protein daily for 7 consecutive days. Oneweek after the completion of LTA4H administration, in week 3, mice inboth treatment groups were injected IP with EdU(5-ethynyl-2′-deoxyuridine) formulated in PBS at a final concentrationof 10 mg/mL and dosed at 50 mg/kg for 5 days. Behavioral assays wereexecuted in week 5 and 6, and animals were sacrificed, and tissuescollected immediately after completion of behavior testing in week 6.FIG. 3 depicts the treatment paradigm and injection timing for thestudy.

Behavior:

FIG. 4 reports the results of the open field testing in mice treatedwith either PBS control or human recombinant LTA4H protein. FIGS. 4A and4B report no change in total distance travelled or average velocitybetween treatment groups. FIG. 4C reports the percent time spent in theperiphery or center of the open field in both treatment groups. All micespend significantly more time in the periphery than in the center of theopen field. Taken together the data indicates that general locomotion asmeasured by total distance travelled and average velocity, and anxietyas measured by percent time spent in periphery or center of the openfield are not affected by treatment with LTA4H. All data shown aremean±s.e.m; ****p<0.0001, Paired t test, n=14.

FIG. 5 depicts the results of fear conditioning testing in mice treatedwith either PBS control or human recombinant LTA4H protein. In thetraining paradigm, mice were placed in the fear conditioning chamber andallowed to explore for 2 min. Then an auditory cue (2000 Hz, 70 dB,conditioned stimulus) was presented for 30 sec, terminating in a 2 secfoot shock (0.6 mA, unconditioned stimulus). This procedure was repeatedonce after a 2 min interval and the mouse was removed from the chamber30 sec after the second shock. 72 hours after training the mouse wasreturned to the same chamber in which the training occurred (memory forcontext) and freezing was recorded for 3 min (Context). 24 hours aftercontext testing the mouse was returned to the same chamber with a novelenvironment (novel context) and freezing was recorded for 2 min(Pre-cue). The auditory cue (2000 Hz, 70 dB, CS) was then presented for30 sec, and freezing was again recorded for 2 min (Post-cue). FIGS. 5Aand 5B show the percent time freezing during the contextual testing,with LTA4H treated mice showing significantly decreased freezingcompared to PBS treated control mice. FIG. 5C shows the percent timefreezing during the cued testing, with both treatment groups showingsignificantly increased freezing after the cue tone, but no significantdifference between treatment groups. The contextual testing measureshippocampal dependent spatial memory and shows that LTA4H treatmentsignificantly impairs the recall of the negative context. Cued testingis administered to determine whether there is a lack of ability toperform the fear conditioning task. Animals in both treatment groupsshow significantly increased freezing after the cue tone, showing thatthey are able to complete the task and show normal fear behavior. Alldata shown are mean±s.e.m; *p<0.05, ***p<0.001, 5B Unpaired t test, 5Cpaired t test, n=14.

Histology:

FIG. 6 reports the number of EdU-labeled cells within the granule celllayer of the dentate gyrus in mice treated with either PBS control orhuman recombinant LTA4H protein. There is a significant decrease in thenumber of EdU-labeled cells in the LTA4H treated animals. This dataindicates that there is a decrease in the number of proliferating cellsthat incorporate the EdU label in week 3 of the treatment paradigm. Alldata shown are mean±s.e.m; *p<0.05, unpaired t test, n=14.

FIG. 7 depicts representative images of cell nuclei labeled with Hoechst33342 (Trihydrochloride trihydrate) and Ki67 antibody labeledproliferating cells in the hippocampus of PBS or recombinant LTA4Htreated mice. There are fewer Ki67 labeled cells in the hippocampus ofLTA4H treated mice than in the PBS treated mice.

FIG. 8 reports the number of Ki67-labeled cells within the granule celllayer of the dentate gyrus in mice treated with either PBS control orhuman recombinant LTA4H protein. There is a significant decrease in thenumber of Ki67-labeled cells in the LTA4H treated animals. This dataindicates that there is a decrease in the number of proliferating cellsthat express Ki67 in study week 6. All data shown are mean±s.e.m;*p<0.05, unpaired t test, n=14.

FIG. 9 reports the results of quantitative polymerase chain reaction(qPCR) quantifying mRNA levels of vesicular glutamate receptor (vglut1),synapsin 1 (syn1), synaptophysin (syp), early growth response 1 (egr1),doublecortin (dcx), beta III tubulin (tuj1), glial acidic fibrillaryprotein (gfap), SRY-Box 2 (sox2), oligodendrocyte transcription factor 2in 3 months old (young) wild-type (C57BL/6) mice treated withrecombinant human LTA4H protein or phosphate buffered saline (PBS)control. There is a significant decrease in egr1 and tuj1 expression.Egr1 is an immediate early gene and a reduction in expression isindicative of a depression of neuronal activity. Tuj1 is a neuronalmarker and the reduction in expression points to detrimental effects onneurons. Furthermore, there is a trend towards a decrease in olig 2, amarker of oligodendrocytes suggesting detrimental effects on this celltype as well. Overall the decreases in neuronal markers and trendstowards decreases in oligodendrocyte markers indicate a detrimentaleffect on neuronal activity and integrity in LTA4H treated animals. Alldata shown are mean±s.e.m; **p<0.01, unpaired t test, n=14.

These results show that there is significant detrimental effect ofperipherally administered human recombinant LTA4H protein onhippocampus-dependent cognition in the contextual fear conditioning testas well as significant detrimental effects on proliferation of neuralstem and progenitor cells in the dentate gyrus of the hippocampus of 3months old wild-type (C57BL/6) mice. Furthermore, there is also adetrimental effect on the expression of the neuronal activity markeregr1 and the mature neuron marker tuj1 indicated additional negativeeffects of peripherally administered LTA4H protein.

The initial study in young, 8-week old wild-type (WT; C57BL/6) mice wasrepeated in a second cohort of mice with additional timepoints andreadouts. Mice were homogenized between 3 treatment groups by bodyweight. Group 1 (Vehicle) was injected intravenously (IV) with PBScontrol 3 times per week for 6 weeks, group 2 (LTA4H Pulse) withrecombinant human LTA4H protein daily for 7 consecutive days, and group3 (LTA4H Continuous) with recombinant human LTA4H protein 3 times perweek for 6 weeks. In week 4 after the initiation of dosing, mice in alltreatment groups were injected IP with BrdU (5-bromo-2′-deoxyuridine)formulated in PBS (phosphate buffered saline) at a final concentrationof 10 mg/mL dosed at 150 mg/kg for 5 days. Behavioral assays wereexecuted in week 5 and 6, and animals were sacrificed, and tissuescollected immediately after completion of behavior testing in week 6.FIG. 10 depicts the treatment paradigm and injection timing for thestudy.

Behavior:

FIG. 11 reports the results of the open field testing in mice treatedwith PBS control, human recombinant LTA4H protein pulse dosing, or humanrecombinant LTA4H protein continuous dosing. FIGS. 11A and 11B report asignificant reduction in distance traveled and average velocity withLTA4H continuous dosing. FIG. 11C reports the percent time spent in theperiphery or center of the open field in both treatment groups. All micespend significantly more time in the periphery than in the center of theopen field. The data indicates that general locomotion as measured bytotal distance travelled and average velocity is impaired withcontinuous dosing of LTA4H, but not with pulse dosing of LTA4H.Additionally, the data indicate that anxiety as measured by percent timespent in periphery or center of the open field are not affected bytreatment with LTA4H with either dosing paradigm. All data shown aremean±s.e.m; Distance and Velocity: One-way ANOVA with multiplecomparisons **p<0.01. Percent time in center vs. periphery, Two-wayANOVA with paired t tests ****p<0.0001. n=14.

FIG. 12 reports the results of the Y-maze behavioral task in micetreated with PBS control, human recombinant LTA4H protein pulse dosing,or human recombinant LTA4H protein continuous dosing. The Y-maze tasktests hippocampus-dependent spatial memory and is designed to haveunique cues in the form of black shapes adhered to walls at the ends oftwo of the arms, while the third is un-cued and designated as thestarting point for the mice. First, mice were individually placed in thestarting arm and allowed to explore only one of the other two arms for 5minutes of training. FIG. 12A reports that there were no differences innumber of entries into the familiar arm between treatment groups duringtraining. During testing, a significant increase in entries into thenovel over the familiar arm signifies contextual memory of the familiararm. FIG. 12B reports that PBS vehicle treated mice had intact memory ofthe familiar arm, while mice treated with LTA4H by pulse or continuousdosing had impaired memory. All data shown are mean±s.e.m; Two-way ANOVAwith paired t tests *p<0.05. n=14.

Histology:

FIG. 13 reports the number of BrdU and DCX co-labeled cells within thegranule cell layer of the dentate gyrus in mice treated with PBS controlor human recombinant LTA4H protein either by pulse or continuous dosing.There is a significant decrease in the number of BrdU/DCX-labeled cellsin the continuously dosed LTA4H treated animals and a statistical trendtowards a decrease in BrdU/DCX-labeled in mice pulse dosed with LTA4H.This data indicates that there is a decrease in the number ofproliferating neuronal cells that incorporate the BrdU label in week 4of the treatment paradigm. All data shown are mean±s.e.m; *p<0.05,unpaired t test, n=14.

FIG. 14 reports the average number of Iba1-labeled cells in thehippocampus of mice treated with PBS control or human recombinant LTA4Hprotein either by pulse or continuous dosing. There is a significantincrease in the number of Iba1-labled cells in mice that are pulseddosed with LTA4H relative to mice dosed with vehicle PBS control. Thisdata indicates that there is an increase in the number of microgliacells, marking an increase in inflammation, upon LTA4H pulse treatment.All data shown are mean±s.e.m; One-way ANOVA with multiple comparisons*p<0.05, n=14.

To test if dosing with recombinant human LTA4H had short-term effects onhistological markers of inflammation, a third cohort of 8-week oldwild-type (WT; C57BL/6) mice was tested 10 days following pulse dosing.Mice were homogenized between 2 treatment groups by body weight. Group 1(Vehicle) was injected intravenously (IV) with PBS control for 7consecutive days and group 2 (LTA4H) with recombinant human LTA4Hprotein daily for 7 consecutive days. BrdU (5-bromo-2′-deoxyuridine)formulated in PBS (phosphate buffered saline) at a final concentrationof 10 mg/mL dosed at 150 mg/kg for 5 days immediately following PBS orLTA4H dosing in week 2. Animals were sacrificed and tissues collected 10days following PBS or LTA4H dosing in week 4. FIG. 15 depicts thetreatment paradigm and injection timing for the study.

Histology:

FIG. 16 reports the average number of CD68-labeled cells in thehippocampus of mice treated with PBS control or human recombinant LTA4Hprotein. There is a significant increase in the number of CD68-labledcells in mice that are pulsed dosed with LTA4H relative to mice dosedwith vehicle PBS control 10 days following dosing. This data indicatesthat there is an increase in the number of activated microglia cells,marking an increase in inflammation, upon LTA4H pulse. All data shownare mean±s.e.m; Unpaired t test *p<0.05, n=14.

E. Example 4

FIG. 17A depicts the signaling pathway of LTA4H enzyme and FIG. 17Bdepicts the key to the diagram in panel A.

Nineteen-month-old (19 mo) wild type (WT; C57BL/6) mice were homogenizedinto five (5) groups by body weight, total distance travelled in theopen field test, and average velocity in the open field test. Group 1was administered 10% EtOH control PO daily for 4 weeks, Group 2 wasadministered 5 mg/kg of SC-57461A LTA4H dual inhibitor PO daily for 4weeks; Group 3 was administered 10 mg/kg of CP-105,696 LTB4 receptor(BLTR) antagonist PO daily for 4 weeks, Group 4 was administered 10mg/kg of Montelukast cysteinyl receptor (CysLTR) antagonist daily for 4weeks, and Group 5 was administered 10 mg/kg of pinostilbene hydratedaily for 4 weeks. During Week 4 of treatment all groups were testedusing open field, radial arm water maze, and Y-maze. During Week 5animals were sacrificed, and tissues collected for histological andbiochemical analysis.

Behavior:

FIG. 18 reports the results of the open field testing. FIGS. 18A and 18Breport no change in total distance travelled or average velocity betweentreatment groups. FIG. 18C reports the percent time spent in theperiphery or center of the open field in all treatment groups. All micespend significantly more time in the periphery than in the center of theopen field. Taken together the data indicates that general locomotion asmeasured by total distance travelled and average velocity, and anxietyas measured by percent time spent in periphery or center of the openfield are not affected by treatment with inhibitors to LTA4H or LTA4Hdownstream effectors. All data shown are mean±s.e.m; ****p<0.0001,Paired t test, n=13-15.

FIG. 19A reports the mean latency for the mice to locate the targetplatform in the radial arm water maze over the course of training andtesting. FIG. 19B reports the mean number of errors made by the mice inlocating the target platform in the radial arm water maze over thecourse of training and testing. FIG. 19C reports the mean latency forthe mice to locate the target platform for last two training trialsdepicted in FIG. 19A. FIG. 19D reports the mean latency for the mice tolocate the target platform for last two testing trials depicted in FIG.19A. FIG. 19E reports the mean number of errors made by the mice inlocating the target platform for last two training trials depicted inFIG. 19B. FIG. 19F reports the mean number of errors for the mice tolocate the target platform for last two testing trials depicted in FIG.19B. All data shown are mean±s.e.m; *p<0.05, **p<0.01 Unpaired t test,n=13-15. Taken together, FIG. 19 reports that there are no differencesin learning between treatment groups and that mice treated with theLTA4H inhibitor SC 57461A or the cysteinyl leukotriene receptorinhibitor Montelukast have an improvement in hippocampus-dependentspatial memory.

FIG. 20A reports the percentage of entries into the novel and familiararms of the Y-maze. The Y-maze task tests hippocampus-dependent memoryand is designed to have unique cues in the form of black shapes adheredto walls at the ends of two of the arms, while the third is un-cued anddesignated as the starting point for the mice. First, mice wereindividually placed in the starting arm and allowed to explore only oneof the other two arms for 5 minutes of training. Then mice are testedwith the novel arm open for exploration. During testing, a significantincrease in entries into the novel over the familiar arm signifiescontextual memory of the familiar arm. Aged mice treated with vehiclecontrol are impaired in the Y-maze and do not have any preference forthe novel versus the familiar arms. Mice treated with the LTA4Hinhibitor SC 57461A have a trend towards preference for the novel armand mice treated with the LTB4 receptor BLTR inhibitor CP 105,696 have astatistically significant preference for the novel arm in this task.FIG. 20B reports the total distance traveled in the Y-maze and there areno differences between treatment groups. Taken together FIG. 20 showsthat inhibition of LTA4H or the LTB4 receptor leads to an improvement inthe hippocampus spatial-dependent memory Y-maze task. All data shown aremean±s.e.m; *p<0.05, Paired t test, n=13-15.

Histology:

FIG. 21A reports the integrated optical density of aquaporin 4 (AQP4) inthe hippocampus. There is a significant decrease in integrated opticaldensity of AQP4 in mice that were treated with the inhibitorsMontelukast and a trend towards a decrease with mice treated with theinhibitor pinostilbene hydrate. This data indicates that there is areduction of aquaporin 4, marking astrocyte end feet, upon LTA4H ordownstream effector inhibition. All data shown are mean±s.e.m; Unpairedt test *p<0.05, n=13-15. FIG. 21B reports the fluorescence intensity ofaquaporin 4 (AQP4) in the hippocampus in the perivascular space. Thereare no changes with any treatment groups. All data shown are mean±s.e.m;n=13-15. FIG. 21C reports the fluorescence intensity of aquaporin 4(AQP4) in the hippocampus in the space immediately surrounding bloodvessels (vascular). There is a trend towards a decrease in thefluorescence intensity AQP4 in mice that were treated with theinhibitors Montelukast and pinostilbene hydrate. All data shown aremean±s.e.m; Unpaired t tests, n=13-15. Together these data indicate thatthere is a reduction of aquaporin 4 surrounding blood vessels in thehippocampus upon LTA4H or downstream effector inhibition.

ELISA:

FIG. 22 reports plasma concentration of LTB4 in pg/mL measured by ELISA.Inhibition of LTA4H with SC 57461A reduces the plasma levels of LTB4.All data shown are mean±s.e.m; *p<0.05, **p<0.01 Unpaired t test,n=13-15.

Gene Expression:

FIG. 23 reports the results of quantitative polymerase chain reaction(qPCR) quantifying the hippocampal mRNA levels of ionizedcalcium-binding adapter molecule 1 (Iba-1), interleukin 6 (IL-6),interleukin 1-beta (IL-1β), Eotaxin, nuclear factorkappa-light-chain-enhancer of activated B cells (NF-κB), and tumornecrosis factor alpha (TNFα) in aged wild-type (C57BL/6) mice treatedwith inhibitors to LTA4H or downstream effectors. FIG. 23B reports asignificant decrease in IL-6 expression in mice treated with the LTA4Hinhibitor SC-5761A. FIG. 23C reports a significant decrease in IL-1βexpression in mice treated with the LTA4H inhibitor SC-5761A and theinhibitor Montelukast. FIG. 23F reports a significant decrease in TNFαexpression in mice treated with the LTA4H inhibitors SC-5761A andpinostilbene hydrate and the inhibitor Montelukast. All data shown aremean±s.e.m; *p<0.05, **p<0.01, Unpaired t test, n=13-15.

FIG. 24A reports the results of quantitative polymerase chain reaction(qPCR) quantifying the hippocampal mRNA levels of the neuronal genesbeta III tubulin (tuj1), synapsin 1 (syn1), post-synaptic densityprotein 95 (dlg4), and brain derived neurotrophic factor (bdnf) in agedwild-type (C57BL/6) mice treated with vehicle or the LTA4H inhibitor SC57461A. All data shown are mean±s.e.m; Unpaired t test, n=13-15.

FIG. 24B reports the results of quantitative polymerase chain reaction(qPCR) quantifying the hippocampal mRNA levels of the microglia genes(total, M1-type, M2-type) cluster of differentiation molecule 11b(CD11b), interleukin 18 (IL-18), cluster of differentiation (CD68),interleukin 1α (IL-1α), interleukin 4 (IL-4), insulin-like growth factor1 (IGF-1), and transforming growth factor β (TGFβ) in aged wild-type(C57BL/6) mice treated with vehicle or the LTA4H inhibitor SC 57461A.All data shown are mean±s.e.m; Unpaired t test, n=13-15.

FIG. 24C reports the results of quantitative polymerase chain reaction(qPCR) quantifying the hippocampal mRNA levels of the astrocytic genes(total, A1-type, A2-type) aquaporin 4 (aqp4), glial acidic fibrillaryprotein (gfap), six transmembrane epithelial antigen of prostate 4(steap4), sphingosine-1-phosphate receptor 1 (slpr3), tissue inhibitorof metalloproteinases (timp1), H2 class I histocompatibility antigen(h2d1), guanylate-binding protein 2 (gbp2), N-acetyllactosaminidealpha-1 3-galactosyltransferase (ggta1), H2T23 protein (h2t23), andcardiotrophin-like cytokine factor 1 (clcf1) in aged wild-type (C57BL/6)mice treated with vehicle or the LTA4H inhibitor SC 57461A. FIG. 24Creports a significant decrease in aqp4 and h2d1 expression in micetreated with the LTA4H inhibitor SC-5761A and a trend towards a decreasein expression of timp1. All data shown are mean±s.e.m; *p<0.05, Unpairedt test, n=13-15.

FIG. 24D reports the results of quantitative polymerase chain reaction(qPCR) quantifying the hippocampal mRNA levels of the immediate earlygenes FBJ osteosarcoma oncogene (cfos), early growth response 1 (egr1),and CAMP responsive element binding protein 1 (creb1) in aged wild-type(C57BL/6) mice treated with vehicle or the inhibitors to LTA4H anddownstream effectors. There is a significant increase in cfos expressionwith mice treated with the inhibitor to cysteinyl leukotriene receptorsMontelukast. Cfos is an immediate early gene and increased geneexpression is indicative of increased neuronal activity. All data shownare mean±s.e.m; **p<0.01, Unpaired t test, n=13-15.

In summary, this example investigated the hypothesis that inhibition ofthe specific detrimental factor LTA4H upregulated in age can improvecognitive deficits in old animals. Specifically, we tested the LTA4Hpathway with the following inhibitors: SC-57461A (LTA4H dual inhibitor),pinostilbene hydrate (LTA4H hydrolase inhibitor), CP-105, 696 (LTB4Receptor1 inhibitor), and Montelukast (cysteinyl leukotriene receptorinhibitor). Montelukast was used as a positive control because it haspreviously been reported to improve cognition and reduce inflammation inaged mice. (Marschallinger J, supra). The results from this studysuggest that there are beneficial effects of LTA4H inhibition oncognitive performance in aged mice, possibly due to a reduction inproinflammatory cytokines in the hippocampus.

Treatment with the LTA4H dual inhibitor SC-57461A resulted inimprovements in the Radial Arm Water Maze test. Treated mice hadsignificantly shorter latency and made fewer errors when compared tovehicle mice during the hidden platform testing phase (FIG. 19D). Ourpositive control Montelukast also showed improvements in this behavior,replicating what has been reported in the literature (Marschallinger, etal. Nature Communications 9 Dec. 2014). To determine the potentialmechanisms for improvements in cognition, we analyzed numeroushistological and biochemical markers in the hippocampus of these mice.There was a significant reduction in the mRNA levels of a number ofproinflammatory cytokines and astrocyte markers, including IL6 IL1b,tnfa, aqp4, and h2d1 (FIG. 21, FIG. 23 and FIG. 24). The gene expressiondata suggests that there may be more subtle changes occurring withmicroglia or astrocytes, which secrete the proinflammatory cytokines.Our positive control Montelukast, showed reductions in many of the sameinflammatory readouts as SC-57461A, as well as, an increase in the mRNAimmediate early gene cfos (FIG. 23 and FIG. 24). Taken together, thesedata suggest that Montelukast may be acting via slightly differentmechanisms to improve cognition.

A secondary question we wanted to answer with this study was regardingthe importance of inhibiting the dual enzymatic activities of LTA4H inaged mice. LTA4H has a hydrolase activity that metabolizes LTA4 to LTB4and it also has a peptidase activity where it digests PGP. (Snelgrove RJ (2010), supra). Previous publications have shown that the hydrolaseactivity of LTA4H produces as a proinflammatory signal, while thepeptidase activity of LTA4H produces an anti-inflammatory signal. (Y.Michael Shim M P, supra; and Snelgrove, R. J. Leukotriene A4 hydrolase:an anti-inflammatory role for a proinflammatory enzyme. Thorax, 66(6):p. 550-51 (2011)). In order to test if the inhibition of the hydrolaseactivity alone was sufficient to see improvements in cognition in agedmice, we included a treatment group with pinostilbene hydrate, which hasbeen reported to only inhibit the hydrolase activity and not thepeptidase activity of LTA4H in vitro. (Low C. M., et al., Thedevelopment of novel LTA4H modulators to selectively target LTB4generation. Sci Rep, 7: p. 44449 (2017)). However, in contrast to thedual inhibitor SC-57461A, we did not detect a reduction in LTB4 levelsin the terminal plasma from mice treated with pinostilbene hydraterelative to vehicle treated mice (FIG. 22), suggesting that our dosingconcentration, frequency, or route of administration was insufficient toinhibit LTA4H in vivo. Therefore, those studies were inconclusive, andit is still unclear the importance of the dual enzyme activities ofLTA4H. Despite not observing a reduction in terminal plasma LTB4, wefound that pinostilbene hydrate did cause a significant reduction inAQP4 levels measured by immunofluorescence (FIG. 21) and in mRNA levelsof tnfa measured by qPCR (FIG. 23F). Therefore, it is possible thepinostilbene hydrate does have some effect on neuroinflammation.

Taken together these data show that inhibition of LTA4H, which isupregulated in human aging, can significantly improve cognitive deficitsand neuroinflammation in aged mice and strongly support the hypothesisthat inhibiting LTA4H in age-related cognitive disease would bebeneficial and effective at improving cognitive function andneuroinflammation.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. Moreover, nothing disclosedherein is intended to be dedicated to the public regardless of whethersuch disclosure is explicitly recited in the claims.

The scope of the present invention, therefore, is not intended to belimited to the exemplary embodiments shown and described herein. Rather,the scope and spirit of present invention is embodied by the appendedclaims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) isexpressly defined as being invoked for a limitation in the claim onlywhen the exact phrase “means for” or the exact phrase “step for” isrecited at the beginning of such limitation in the claim; if such exactphrase is not used in a limitation in the claim, then 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) is not invoked.

1. A method of improving cognitive function in a subject diagnosed withan age-related cognitive disease, the method comprising administering atherapeutically effective amount of an LTA4H modulatory agent.
 2. Themethod of claim 1 wherein the cognitive disease is from the groupconsisting of Alzheimer's Disease, mild cognitive impairment,Parkinson's Disease, Parkinsonism, Frontotemporal dementia, Huntington'sDisease, amyotrophic lateral sclerosis, multiple sclerosis, dementia,dementia with Lewy bodies, and progressive supranuclear palsy.
 3. Themethod of claim 1 wherein the LTA4H modulatory agent is a small organicmolecule antagonist to LTA4H.
 4. The method of claim 1 wherein the LTA4Hmodulatory agent is an antibody to LTA4H.
 5. The method of claim 3wherein the antagonist to LTA4H antagonizes the epoxide hydrolaseactivity of LTA4H.
 6. The method of claim 3 wherein the antagonist toLTA4H antagonizes both the epoxide hydrolase activity and theaminopeptidase activity of LTA4H.
 7. The method of claim 1 wherein thesubject is a mammal.
 8. The method of claim 7 wherein the mammal is ahuman.
 9. A kit for use in improving cognitive function in a subjectdiagnosed with an age-related cognitive disease, the kit comprising anLTA4H modulatory agent.
 10. The kit of claim 9 wherein the LTA4Hmodulatory agent is a small organic molecule antagonist to LTA4H. 11.The kit of claim 9 wherein the LTA4H modulatory agent is an antibody toLTA4H.
 12. The kit of claim 11 wherein the antagonist to LTA4Hantagonizes the epoxide hydrolase activity of LTA4H.
 13. The kit ofclaim 12 wherein the antagonist to LTA4H antagonizes both the epoxidehydrolase activity and the aminopeptidase activity of LTA4H.